DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	PDGFRB (QuickGO)	Interactive visualization of PDGFRB structures (A quick tutorial to explore the interctive visulaization) Representative structure: 2PLE
Synonyms	PDGFRB, PDGFR, PDGFR1
Protein Name	PDGFRB
Alternative Name(s)	Platelet-derived growth factor receptor beta;PDGF-R-beta;PDGFR-beta;2.7.10.1;Beta platelet-derived growth factor receptor;Beta-type platelet-derived growth factor receptor;CD140 antigen-like family member B;Platelet-derived growth factor receptor 1;PDGFR-1;CD140b;
Protein Family	Belongs to the protein kinase superfamily Tyr proteinkinase family CSF-1/PDGF receptor subfamily
EntrezGene ID	5159 (Comparitive Toxicogenomics)
UniProt AC (Human)	P09619 (protein sequence)
Enzyme Class	2.7.10.1 (BRENDA )
Molecular Weight	123968 Dalton
Protein Length	1106 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000113721 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0200 \| eggNOG - COG0515
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Cell membrane; Single-pass type I membraneprotein Cytoplasmic vesicle Lysosome lumen Note=After ligandbinding, the autophosphorylated receptor is ubiquitinated andinternalized, leading to its degradation
Function (UniProt annotation)
Tyrosine-protein kinase that acts as cell-surfacereceptor for homodimeric PDGFB and PDGFD and for heterodimersformed by PDGFA and PDGFB, and plays an essential role in theregulation of embryonic development, cell proliferation, survival,differentiation, chemotaxis and migration Plays an essential rolein blood vessel development by promoting proliferation, migrationand recruitment of pericytes and smooth muscle cells toendothelial cells Plays a role in the migration of vascularsmooth muscle cells and the formation of neointima at vascularinjury sites Required for normal development of thecardiovascular system Required for normal recruitment ofpericytes (mesangial cells) in the kidney glomerulus, and fornormal formation of a branched network of capillaries in kidneyglomeruli Promotes rearrangement of the actin cytoskeleton andthe formation of membrane ruffles Binding of its cognate ligands- homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB orhomodimeric PDGFD -leads to the activation of several signalingcascades; the response depends on the nature of the bound ligandand is modulated by the formation of heterodimers between PDGFRAand PDGFRB Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL,SHC1 and NCK1 Activation of PLCG1 leads to the production of thecellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activationof protein kinase C Phosphorylation of PIK3R1, the regulatorysubunit of phosphatidylinositol 3-kinase, leads to the activationof the AKT1 signaling pathway Phosphorylation of SHC1, or of theC-terminus of PTPN11, creates a binding site for GRB2, resultingin the activation of HRAS, RAF1 and down-stream MAP kinases,including MAPK1/ERK2 and/or MAPK3/ERK1 Promotes phosphorylationand activation of SRC family kinases Promotes phosphorylation ofPDCD6IP/ALIX and STAM Receptor signaling is down-regulated byprotein phosphatases that dephosphorylate the receptor and itsdown-stream effectors, and by rapid internalization of theactivated receptor
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Protein Sequence
MRLPGAMPALALKGELLLLSLLLLLEPQISQGLVVTPPGPELVLNVSSTFVLTCSGSAPVVWERMSQEPPQEMAKAQDGT FSSVLTLTNLTGLDTGEYFCTHNDSRGLETDERKRLYIFVPDPTVGFLPNDAEELFIFLTEITEITIPCRVTDPQLVVTL HEKKGDVALPVPYDHQRGFSGIFEDRSYICKTTIGDREVDSDAYYVYRLQVSSINVSVNAVQTVVRQGENITLMCIVIGN EVVNFEWTYPRKESGRLVEPVTDFLLDMPYHIRSILHIPSAELEDSGTYTCNVTESVNDHQDEKAINITVVESGYVRLLG EVGTLQFAELHRSRTLQVVFEAYPPPTVLWFKDNRTLGDSSAGEIALSTRNVSETRYVSELTLVRVKVAEAGHYTMRAFH EDAEVQLSFQLQINVPVRVLELSESHPDSGEQTVRCRGRGMPQPNIIWSACRDLKRCPRELPPTLLGNSSEEESQLETNV TYWEEEQEFEVVSTLRLQHVDRPLSVRCTLRNAVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKKP RYEIRWKVIESVSSDGHEYIYVDPMQLPYDSTWELPRDQLVLGRTLGSGAFGQVVEATAHGLSHSQATMKVAVKMLKSTA RSSEKQALMSELKIMSHLGPHLNVVNLLGACTKGGPIYIITEYCRYGDLVDYLHRNKHTFLQHHSDKRRPPSAELYSNAL PVGLPLPSHVSLTGESDGGYMDMSKDESVDYVPMLDMKGDVKYADIESSNYMAPYDNYVPSAPERTCRATLINESPVLSY MDLVGFSYQVANGMEFLASKNCVHRDLAARNVLICEGKLVKICDFGLARDIMRDSNYISKGSTFLPLKWMAPESIFNSLY TTLSDVWSFGILLWEIFTLGGTPYPELPMNEQFYNAIKRGYRMAQPAHASDEIYEIMQKCWEEKFEIRPPFSQLVLLLER LLGEGYKKKYQQVDEEFLRSDHPAILRSQARLPGFHGLRSPLDTSSVLYTAVQPNEGDNDYIIPLPDPKPEVADEGPLEG SPSLASSTLNEVNTSSTISCDSPLEPQDEPEPEPQLELQVEPEPELEQLPDSGCPAPRAEAEDSFL

Motif information from Eukaryotic Linear Motif atlas (ELM)

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Gene Ontology (P: Process; F: Function and C: Component terms)

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GO:0000165	P:MAPK cascade
GO:0004713	F:protein tyrosine kinase activity
GO:0004992	F:platelet activating factor receptor activity
GO:0005017	F:platelet-derived growth factor-activated receptor activity
GO:0005019	F:platelet-derived growth factor beta-receptor activity
GO:0005088	F:Ras guanyl-nucleotide exchange factor activity
GO:0005102	F:signaling receptor binding
GO:0005161	F:platelet-derived growth factor receptor binding
GO:0005524	F:ATP binding
GO:0005634	C:nucleus
GO:0005737	C:cytoplasm
GO:0005794	C:Golgi apparatus
GO:0005886	C:plasma membrane
GO:0005925	C:focal adhesion
GO:0006024	P:glycosaminoglycan biosynthetic process
GO:0007165	P:signal transduction
GO:0007568	P:aging
GO:0008284	P:positive regulation of cell proliferation
GO:0008584	P:male gonad development
GO:0009986	C:cell surface
GO:0010863	P:positive regulation of phospholipase C activity
GO:0014068	P:positive regulation of phosphatidylinositol 3-kinase signaling
GO:0014911	P:positive regulation of smooth muscle cell migration
GO:0016020	C:membrane
GO:0016021	C:integral component of membrane
GO:0016324	C:apical plasma membrane
GO:0016477	P:cell migration
GO:0018108	P:peptidyl-tyrosine phosphorylation
GO:0019899	F:enzyme binding
GO:0019901	F:protein kinase binding
GO:0030335	P:positive regulation of cell migration
GO:0031226	C:intrinsic component of plasma membrane
GO:0031410	C:cytoplasmic vesicle
GO:0032355	P:response to estradiol
GO:0032516	P:positive regulation of phosphoprotein phosphatase activity
GO:0032526	P:response to retinoic acid
GO:0032956	P:regulation of actin cytoskeleton organization
GO:0032967	P:positive regulation of collagen biosynthetic process
GO:0034405	P:response to fluid shear stress
GO:0035025	P:positive regulation of Rho protein signal transduction
GO:0035441	P:cell migration involved in vasculogenesis
GO:0035789	P:metanephric mesenchymal cell migration
GO:0035791	P:platelet-derived growth factor receptor-beta signaling pathway
GO:0035793	P:positive regulation of metanephric mesenchymal cell migration by platelet-derived growth factor receptor-beta signaling pathway
GO:0035909	P:aorta morphogenesis
GO:0038085	F:vascular endothelial growth factor binding
GO:0038091	P:positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway
GO:0042060	P:wound healing
GO:0042542	P:response to hydrogen peroxide
GO:0043065	P:positive regulation of apoptotic process
GO:0043066	P:negative regulation of apoptotic process
GO:0043202	C:lysosomal lumen
GO:0043231	C:intracellular membrane-bounded organelle
GO:0043406	P:positive regulation of MAP kinase activity
GO:0043548	F:phosphatidylinositol 3-kinase binding
GO:0043552	P:positive regulation of phosphatidylinositol 3-kinase activity
GO:0043627	P:response to estrogen
GO:0045840	P:positive regulation of mitotic nuclear division
GO:0046488	P:phosphatidylinositol metabolic process
GO:0046777	P:protein autophosphorylation
GO:0046934	F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0048008	P:platelet-derived growth factor receptor signaling pathway
GO:0048015	P:phosphatidylinositol-mediated signaling
GO:0048146	P:positive regulation of fibroblast proliferation
GO:0048407	F:platelet-derived growth factor binding
GO:0048661	P:positive regulation of smooth muscle cell proliferation
GO:0048839	P:inner ear development
GO:0050921	P:positive regulation of chemotaxis
GO:0051897	P:positive regulation of protein kinase B signaling
GO:0055003	P:cardiac myofibril assembly
GO:0055093	P:response to hyperoxia
GO:0060326	P:cell chemotaxis
GO:0060437	P:lung growth
GO:0060981	P:cell migration involved in coronary angiogenesis
GO:0061298	P:retina vasculature development in camera-type eye
GO:0070374	P:positive regulation of ERK1 and ERK2 cascade
GO:0071670	P:smooth muscle cell chemotaxis
GO:0072075	P:metanephric mesenchyme development
GO:0072262	P:metanephric glomerular mesangial cell proliferation involved in metanephros development
GO:0072277	P:metanephric glomerular capillary formation
GO:0072278	P:metanephric comma-shaped body morphogenesis
GO:0072284	P:metanephric S-shaped body morphogenesis
GO:0090280	P:positive regulation of calcium ion import
GO:2000379	P:positive regulation of reactive oxygen species metabolic process
GO:2000491	P:positive regulation of hepatic stellate cell activation
GO:2000573	P:positive regulation of DNA biosynthetic process

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa01521	EGFR tyrosine kinase inhibitor resistance	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.
hsa04010	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
hsa04014	Ras signaling pathway	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).
hsa04015	Rap1 signaling pathway	Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
hsa04020	Calcium signaling pathway	Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs).The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it.The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM).
hsa04072	Phospholipase D signaling pathway	Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2). The PLD-produced PA activates signaling proteins and acts as a node within the membrane to which signaling proteins translocate. Several signaling proteins, including Raf-1 and mTOR, directly bind PA to mediate translocation or activation, respectively.
hsa04151	PI3K-Akt signaling pathway	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.
hsa04510	Focal adhesion	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.
hsa04540	Gap junction	Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.
hsa04630	Jak-STAT signaling pathway	The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.
hsa04810	Regulation of actin cytoskeleton
hsa05165	Human papillomavirus infection	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.
hsa05166	Human T-cell leukemia virus 1 infection	Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, SRF, and NFAT.
hsa05200	Pathways in cancer
hsa05206	MicroRNAs in cancer	MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or the inhibition of protein translation. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer. The upregulation (overexpression) of specific miRNAs could lead to the repression of tumor suppressor gene expression, and conversely the downregulation of specific miRNAs could result in an increase of oncogene expression; both these situations induce subsequent malignant effects on cell proliferation, differentiation, and apoptosis that lead to tumor growth and progress. The miRNA signatures of cancer observed in various studies differ significantly. These inconsistencies occur due to the differences in the study populations and methodologies used. This pathway map shows the summarized results from various studies in 9 cancers, each of which is presented in a review article.
hsa05214	Glioma	Gliomas are the most common of the primary brain tumors and account for more than 40% of all central nervous system neoplasms. Gliomas include tumours that are composed predominantly of astrocytes (astrocytomas), oligodendrocytes (oligodendrogliomas), mixtures of various glial cells (for example,oligoastrocytomas) and ependymal cells (ependymomas). The most malignant form of infiltrating astrocytoma - glioblastoma multiforme (GBM) - is one of the most aggressive human cancers. GBM may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas develop in older patients and typically show genetic alterations (EGFR amplification, p16/INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients and frequently show overexpression of PDGF and CDK4 as well as p53 mutations (65%) and loss of Rb playing major roles in such transformations. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.
hsa05215	Prostate cancer	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.
hsa05218	Melanoma	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.
hsa05230	Central carbon metabolism in cancer	Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.
hsa05231	Choline metabolism in cancer	Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-1257604	PIP3 activates AKT signaling.	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007
R-HSA-186763	Downstream signal transduction.	The role of autophosphorylation sites on PDGF receptors are to provide docking sites for downstream signal transduction molecules which contain SH2 domains. The SH2 domain is a conserved motif of around 100 amino acids that can bind a phosphorylated tyrosine residue. These downstream molecules are activated upon binding to, or phosphorylated by, the receptor kinases intrinsic to PDGF receptors.Some of the dowstream molecules are themselves enzymes, such as phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC-gamma), the Src family of tyrosine kinases, the tyrosine phosphatase SHP2, and a GTPase activating protein (GAP) for Ras. Others such as Grb2 are adaptor molecules which link the receptor with downstream catalytic molecules
R-HSA-186797	Signaling by PDGF.	Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer.	Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
R-HSA-5673001	RAF/MAP kinase cascade.	The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011)
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.	Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase

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PDGFRB