241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
299 KEGG pathways;
876 Reactome pathways;
last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Mitochondrion outer membrane Cytoplasm Note=Colocalizes with HIF3A in thecytoplasm (By similarity) Upon phosphorylation, locates to thecytoplasm
Function (UniProt annotation)
Promotes cell death Successfully competes for thebinding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the levelof heterodimerization of these proteins with BAX Can reverse thedeath repressor activity of Bcl-X(L), but not that of Bcl-2 (Bysimilarity) Appears to act as a link between growth factorreceptor signaling and the apoptotic pathways
EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR also serves as a stimulus for cancer growth. EGFR gene mutations and protein overexpression, both of which activate down- stream pathways, are associated with cancers, especially lung cancer. Several tyrosine kinase inhibitor (TKI) therapies against EGFR are currently administered and are initially effective in cancer patients who have EGFR mutations or aberrant activation of EGFR. However, the development of TKI resistance is common and results in the recurrence of tumors. Studies over the last decade have identified mechanisms that drive resistance to EGFR TKI treatment. Most outstanding mechanisms are: the secondary EGFR mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, etc.
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. The most commonly used endocrine therapy agents are selective estrogen receptor modulators (SERMs, e.g. tamoxifen), estrogen synthesis inhibitors (e.g. aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane), and selective estrogen receptor down-regulators (SERDs, e.g. fulvestrant). However, resistance to these agents has become a major clinical obstacle. Mechanisms of endocrine resistance include loss of ER-alpha expression, altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes, such as CYP2D6, and deregulation of the cell cycle and apoptotic machinery.
Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. The mechanism of action of Platinum-based drugs involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Platinum resistance could arise from decreased drug influx, increased drug efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), increased DNA repair, decreased mismatch repair, defective apoptosis, and altered oncogene expression.
The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.
The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
Cyclic GMP (cGMP) is the intracellular second messenger that mediates the action of nitric oxide (NO) and natriuretic peptides (NPs), regulating a broad array of physiologic processes. The elevated intracellular cGMP level exerts its physiological action through two forms of cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels, among which PKGs might be the primary mediator. PKG1 isoform-specific activation of established substrates leads to reduction of cytosolic calcium concentration and/or decrease in the sensitivity of myofilaments to Ca2+ (Ca2+-desensitization), resulting in smooth muscle relaxation. In cardiac myocyte, PKG directly phosphorylates a member of the transient potential receptor canonical channel family, TRPC6, suppressing this nonselective ion channel's Ca2+ conductance, G-alpha-q agonist-induced NFAT activation, and myocyte hypertrophic responses. PKG also opens mitochondrial ATP-sensitive K+ (mitoKATP) channels and subsequent release of ROS triggers cardioprotection.
cAMP is one of the most common and universal second messengers, and its formation is promoted by adenylyl cyclase (AC) activation after ligation of G protein-coupled receptors (GPCRs) by ligands including hormones, neurotransmitters, and other signaling molecules. cAMP regulates pivotal physiologic processes including metabolism, secretion, calcium homeostasis, muscle contraction, cell fate, and gene transcription. cAMP acts directly on three main targets: protein kinase A (PKA), the exchange protein activated by cAMP (Epac), and cyclic nucleotide-gated ion channels (CNGCs). PKA modulates, via phosphorylation, a number of cellular substrates, including transcription factors, ion channels, transporters, exchangers, intracellular Ca2+ -handling proteins, and the contractile machinery. Epac proteins function as guanine nucleotide exchange factors (GEFs) for both Rap1 and Rap2. Various effector proteins, including adaptor proteins implicated in modulation of the actin cytoskeleton, regulators of G proteins of the Rho family, and phospholipases, relay signaling downstream from Rap.
Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.
Autophagy (or macroautophagy) is a cellular catabolic pathway involving in protein degradation, organelle turnover, and non-selective breakdown of cytoplasmic components, which is evolutionarily conserved among eukaryotes and exquisitely regulated. This progress initiates with production of the autophagosome, a double-membrane intracellular structure of reticular origin that engulfs cytoplasmic contents and ultimately fuses with lysosomes for cargo degradation. Autophagy is regulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation and ER stress. Constitutive level of autophagy plays an important role in cellular homeostasis and maintains quality control of essential cellular components.
The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.
Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling.
Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
The thyroid hormones (THs) are important regulators of growth, development and metabolism. The action of TH is mainly mediated by T3 (3,5,3'-triiodo-L-thyronine). Thyroid hormones, L-thyroxine (T4) and T3 enter the cell through transporter proteins. Although the major form of TH in the blood is T4, it is converted to the more active hormone T3 within cells. T3 binds to nuclear thyroid hormone receptors (TRs), which functions as a ligand-dependent transcription factor and controls the expression of target genes (genomic action). Nongenomic mechanisms of action is initiated at the integrin receptor. The plasma membrane alpha(v)beta(3)-integrin has distinct binding sites for T3 and T4. One binding site binds only T3 and activates the phosphatidylinositol 3-kinase (PI3K) pathway. The other binding site binds both T3 and T4 and activates the ERK1/2 MAP kinase pathway.
Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial ALS (FALS) cases, is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS). Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess increases intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions , which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, affecting axonal transport. Collectively, these mechanisms are predicted to disturb cellular homeostasis, ultimately triggering motor neuron death.
Toxoplasma gondii is an obligate intracellular parasite that is prevalent worldwide. The tachyzoite form acquired by oral ingestion downmodulates proinflammatory signaling pathways via various mechanisms. During early infection, nuclear translocation of NFkB is temporally blocked and p38 MAPK phosphorylation is prevented, suppressing IL-12 production. Another pathway for IL-12 induction occurs through CCR5 dependent pathway, but parasitic induction of an eicosanoid LXA4 contributes to the downregulation of IL-12. Direct activation of STAT3 by the parasite enhance anti-inflammatory function of IL-10 and TGF beta. T. gondii can cause lifelong chronic infection by establishing an anti-apoptotic environment through induction of bcl-2 or IAPs and by redirecting LDL-mediated cholesterol transport to scavenge nutrients from the host.
Tuberculosis, or TB, is an infectious disease caused by Mycobacterium tuberculosis. One third of the world's population is thought to be infected with TB. About 90% of those infected result in latent infections, and about 10% of latent infections develop active diseases when their immune system is impaired due to the age, other diseases such as AIDS or exposure to immunosuppressive drugs. TB is transmitted through the air and primarily attacks the lungs, then it can spread by the circulatory system to other parts of body. Once TB bacilli have entered the host by the respiratory route and infected macrophages in the lungs, they interfere with phagosomal maturation, antigen presentation, apoptosis and host immune system to establish persistent or latent infection.
Hepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the cytoplasm of the host cell and forms membrane-associated replication complexes along with non-structural proteins. Viral RNA can trigger the RIG-I pathway and interferon production during this process. Translated HCV protein products regulate immune response to inhibit the action of interferon. HCV core and NS5A proteins appear to be the most important molecules with regulatory functions that modulate transcription, cellular proliferation, and apoptosis.
Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.
Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.
Human immunodeficiency virus type 1 (HIV-1) , the causative agent of AIDS (acquired immunodeficiency syndrome), is a lentivirus belonging to the Retroviridae family. The primary cell surface receptor for HIV-1, the CD4 protein, and the co-receptor for HIV-1, either CCR5 or CXCR4, are found on macrophages and T lymphocytes. At the earliest step, sequential binding of virus envelope (Env) glycoprotein gp120 to CD4 and the co-receptor CCR5 or CXCR4 facilitates HIV-1 entry and has the potential to trigger critical signaling that may favor viral replication. At advanced stages of the disease, HIV-1 infection results in dramatic induction of T-cell (CD4+ T and CD8+ T cell) apoptosis both in infected and uninfected bystander T cells, a hallmark of HIV-1 pathogenesis. On the contrary, macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time.
There is a strong association between viruses and the development of human malignancies. We now know that at least six human viruses, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) contribute to 10-15% of the cancers worldwide. Via expression of many potent oncoproteins, these tumor viruses promote an aberrant cell-proliferation via modulating cellular cell-signaling pathways and escape from cellular defense system such as blocking apoptosis. Human tumor virus oncoproteins can also disrupt pathways that are necessary for the maintenance of the integrity of host cellular genome. Viruses that encode such activities can contribute to initiation as well as progression of human cancers.
Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).
Renal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases. RCC is not a single disease, it has several morphological subtypes. Conventional RCC (clear cell RCC) accounts for ~80% of cases, followed by papillary RCC (10-15%), chromophobe RCC (5%), and collecting duct RCC (<1%). Genes potentially involved in sporadic neoplasms of each particular type are VHL, MET, BHD, and FH respectively. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. Activated MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC.
Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
Endometrial cancer (EC) is the most common gynaecological malignancy and the fourth most common malignancy in women in the developed world after breast, colorectal and lung cancer. Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy, p53 mutations, and her2/neu amplification.
Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.
Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1. Additional chromosome translocations are also observed,such as t(3;21)(q26;q22), which generates AML1-EVI1.
Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.
The switching on/off of its phosphorylation by growth/survival factors regulates BAD activity. BAD remains sequestered by 14-3-3 scaffold proteins after phosphorylation by Akt1. Calcineurin activates BAD by dephosphorylation
Bcl-2 interacts with tBid (Yi et al. 2003), BIM (Puthalakath et al. 1999), PUMA (Nakano and Vousden 2001), NOXA (Oda et al. 2000), BAD (Yang et al. 2005), BMF (Puthalakath et al. 2001), resulting in inactivation of BCL2. Binding of BCL2 to tBID inhibits BID-induced cytochrome C release and apoptosis (Yi et al. 2003). BH3 only proteins associate with and inactivate anti-apoptotic BCL-XL
Once bound by either NGF or proNGF, p75NTR interacts with NRAGE, thus leading to phosphorylation and activation of JUN Kinase (JNK). JNK controls apoptosis in two ways: it induces transcription of pro-apoptotic genes, and directly activates the cell death machinery. Only NGF-bound p75NTR is shown here
Following activation, AKT can phosphorylate an array of target proteins in the cytoplasm, many of which are involved in cell survival control. Phosphorylation of TSC2 feeds positively to the TOR kinase, which, in turn, contributes to AKT activation (positive feedback loop)
While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008)