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Human Phosphatases
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Statistics

241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update:
11 Mar, 2019
last maintenance update:
01 Sep, 2023

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ARHGAP35

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	ARHGAP35 (QuickGO)	Interactive visualization of ARHGAP35 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 2K85
Synonyms	ARHGAP35 , GRF1
Protein Name	ARHGAP35
Alternative Name(s)	Rho GTPase-activating protein 35;Glucocorticoid receptor DNA-binding factor 1;Glucocorticoid receptor repression factor 1;GRF-1;Rho GAP p190A;p190-A;
Protein Family	noSimilarity_annotations
EntrezGene ID	2909 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q9NRY4 (protein sequence)
Enzyme Class	N/A
Molecular Weight	170514 Dalton
Protein Length	1499 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000160007 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG4271 \| eggNOG - ENOG410XR4E
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

Localization, Function, Catalytic activity and Sequence

Localization (UniProt annotation)
Cytoplasm, cytoskeleton, cilium basal body Cytoplasm Nucleus Cell membrane Note=In response to integrins andSDC4 and upon phosphorylation by PKC, relocalizes from thecytoplasm to regions of plasma membrane ruffling where itcolocalizes with polymerized actin
Function (UniProt annotation)
Rho GTPase-activating protein (GAP) (PubMed:19673492,PubMed:28894085) Binds several acidic phospholipids whichinhibits the Rho GAP activity to promote the Rac GAP activity(PubMed:19673492) This binding is inhibited by phosphorylation byPRKCA (PubMed:19673492) Involved in cell differentiation as wellas cell adhesion and migration, plays an important role in retinaltissue morphogenesis, neural tube fusion, midline fusion of thecerebral hemispheres and mammary gland branching morphogenesis (Bysimilarity) Transduces signals from p21-ras to the nucleus,acting via the ras GTPase-activating protein (GAP) (Bysimilarity) Transduces SRC-dependent signals from cell-surfaceadhesion molecules, such as laminin, to promote neurite outgrowthRegulates axon outgrowth, guidance and fasciculation (Bysimilarity) Modulates Rho GTPase-dependent F-actinpolymerization, organization and assembly, is involved inpolarized cell migration and in the positive regulation ofciliogenesis and cilia elongation (By similarity) During mammarygland development, is required in both the epithelial and stromalcompartments for ductal outgrowth (By similarity) Repressestranscription of the glucocorticoid receptor by binding to thecis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; thisfunction is however unclear and would need additional experimentalevidences (PubMed:1894621)
Catalytic Activity (UniProt annotation)
N/A
Protein Sequence
MMMARKQDVRIPTYNISVVGLSGTEKEKGQCGIGKSCLCNRFVRPSADEFHLDHTSVLSTSDFGGRVVNNDHFLYWGEVS RSLEDCVECKMHIVEQTEFIDDQTFQPHRSTALQPYIKRAAATKLASAEKLMYFCTDQLGLEQDFEQKQMPDGKLLVDGF LLGIDVSRGMNRNFDDQLKFVSNLYNQLAKTKKPIVVVLTKCDEGVERYIRDAHTFALSKKNLQVVETSARSNVNVDLAF STLVQLIDKSRGKTKIIPYFEALKQQSQQIATAKDKYEWLVSRIVKNHNENWLSVSRKMQASPEYQDYVYLEGTQKAKKL FLQHIHRLKHEHIERRRKLYLAALPLAFEALIPNLDEIDHLSCIKAKKLLETKPEFLKWFVVLEETPWDATSHIDNMENE RIPFDLMDTVPAEQLYEAHLEKLRNERKRVEMRRAFKENLETSPFITPGKPWEEARSFIMNEDFYQWLEESVYMDIYGKH QKQIIDKAKEEFQELLLEYSELFYELELDAKPSKEKMGVIQDVLGEEQRFKALQKLQAERDALILKHIHFVYHPTKETCP SCPACVDAKIEHLISSRFIRPSDRNQKNSLSDPNIDRINLVILGKDGLARELANEIRALCTNDDKYVIDGKMYELSLRPI EGNVRLPVNSFQTPTFQPHGCLCLYNSKESLSYVVESIEKSRESTLGRRDNHLVHLPLTLILVNKRGDTSGETLHSLIQQ GQQIASKLQCVFLDPASAGIGYGRNINEKQISQVLKGLLDSKRNLNLVSSTASIKDLADVDLRIVMCLMCGDPFSADDIL FPVLQSQTCKSSHCGSNNSVLLELPIGLHKKRIELSVLSYHSSFSIRKSRLVHGYIVFYSAKRKASLAMLRAFLCEVQDI IPIQLVALTDGAVDVLDNDLSREQLTEGEEIAQEIDGRFTSIPCSQPQHKLEIFHPFFKDVVEKKNIIEATHMYDNAAEA CSTTEEVFNSPRAGSPLCNSNLQDSEEDIEPSYSLFREDTSLPSLSKDHSKLSMELEGNDGLSFIMSNFESKLNNKVPPP VKPKPPVHFEITKGDLSYLDQGHRDGQRKSVSSSPWLPQDGFDPSDYAEPMDAVVKPRNEEENIYSVPHDSTQGKIITIR NINKAQSNGSGNGSDSEMDTSSLERGRKVSIVSKPVLYRTRCTRLGRFASYRTSFSVGSDDELGPIRKKEEDQASQGYKG DNAVIPYETDEDPRRRNILRSLRRNTKKPKPKPRPSITKATWESNYFGVPLTTVVTPEKPIPIFIERCIEYIEATGLSTE GIYRVSGNKSEMESLQRQFDQDHNLDLAEKDFTVNTVAGAMKSFFSELPDPLVPYNMQIDLVEAHKINDREQKLHALKEV LKKFPKENHEVFKYVISHLNKVSHNNKVNLMTSENLSICFWPTLMRPDFSTMDALTATRTYQTIIELFIQQCPFFFYNRP ITEPPGARPSSPSAVASTVPFLTSTPVTSQPSPPQSPPPTPQSPMQPLLPSQLQAEHTL

Motif information from Eukaryotic Linear Motif atlas (ELM)

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

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
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.
hsa04611	Platelet activation	Platelets play a key and beneficial role for primary hemostasis on the disruption of the integrity of vessel wall. Platelet adhesion and activation at sites of vascular wall injury is initiated by adhesion to adhesive macromolecules, such as collagen and von Willebrand factor (vWF), or by soluble platelet agonists, such as ADP, thrombin, and thromboxane A2. Different receptors are stimulated by various agonists, almost converging in increasing intracellular Ca2+ concentration that stimulate platelet shape change and granule secretion and ultimately induce the inside-outsignaling process leading to activation of the ligand-binding function of integrin alpha IIb beta 3. Binding of alpha IIb beta 3 to its ligands, mainly fibrinogen, mediates platelet adhesion and aggregation and triggers outside-insignaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction.
hsa04670	Leukocyte transendothelial migration	Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passagethrough which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.
hsa04810	Regulation of actin cytoskeleton

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-194840	Rho GTPase cycle.	The cycling of Rho GTPases is tightly controlled by three classes of protein. These are (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase Activating Proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities. In their active GTP-bound state, Rho family members have the ability to interact with a large variety of so-called effector proteins. By changing the subcellular localization of effectors, by altering their enzymatic properties, or by directing the formation of specific effector complexes, members of the Rho family mediate their various effects. This Rho GTPase cycle is diagrammed in the figure below. External or internal cues promote the release of Rho GTPases from the inhibitory complex (1) which allows them to associate with the plasma membrane (2) where they are activated by GEFs (3) and can signal to effector proteins. Then, GAPs inactivate the GTPases by accelerating the intrinsic GTPase activity, leading to the GDP bound form (4). Once again, the GDI molecules stabilize the inactive GDP bound form in the cytoplasm, waiting for further instructions (5). (Figure and text from Tcherkezian and Lamarche Vane, 2007)
R-HSA-416550	Sema4D mediated inhibition of cell attachment and migration.	Repulsive Sema4D-Plexin-B1 signaling involves four GTPases, Rnd1, R-Ras, Rho and Rac1. Sema4D-Plexin-B1 binding promotes Rnd1-dependent activation of the plexin-B1 GAP domain and transient suppression of R-Ras activity. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP2 inactivation. Plexin-B1 also transiently associates with and activates p190Rho-GAP, triggering a transient decrease in activated Rho
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.	PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008). PTK6 inhibits RAS GTPase activating protein RASA1 (Shen et al. 2008) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al