Summary of Important Herceptin Resistant Genes
(Reported to be Involved in Resistance)

In past number of genes have been reported in literature to be involved or effect herceptin resistance/sensitivity. These genes may effect Herceptin senitivity by expression (over/under) or mutation of certain genes.

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Serial No. Protein Name Synonym Protein description                  Resistance Due to Uniprot ID RwefSeq IDs Detail                                                                                                                             
1PTENMMAC1, TEP1Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN)(Phosphatase and tensin homologMutationP60484NM_00031Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4. The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with AIP1 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. LOSS OF PTEN EXPRESSION AND ACTIVATION OF PI3K PATHWAY CREATES RESISTANCE TO DRUGS TARGETING HER2 TYROSINE KINASE SIGNALING
2BRCA1Breast cancer type 1 susceptibility protein MutationQ1RMC1NM_007300BRCA1 is responsible for several cellular functions, withparticular emphasis related to sensing DNA damage. BRCA1 mediates HR via the formation of RAD51 nuclear foci. HR is thus responsible for repair of stalled replication forks and DNA DSBs. The absence of a functional BRCA1 gene consequently renders the cell incapable of repairing DNA DSBs by HR and the cellular machinery becomes dependent uponmore error-prone methods of DNA DSBs repair—NHEJ andSSA. Accordingly, loss of a functional BRCA1 gene, viaa mutation, epigenetic silencing, or enhanced transcription ofa negative regulator of BRCA1, promotes chromosomalinstability and often results in carcinogenesis. Gene expression profiling has revealed that tumors from patients who are BRCA1 mutated segregate within the basalsubgroup of breast cancers . Tumors from BRCA1 mutationcarriers are likely to stain positive for basal cytokeratins 5/6 and14 and to exhibit negative estrogen receptor staining. Thesebreast carcinomas also commonly stain for epidermal growthfactor receptor. BRCA1-associated tumors are commonlyhigh grade and p53 mutated. They also have a tendency tooccur in younger women and carry a poor prognosis .Tumors arising in a BRCA1 mutation background mostoften display a basal-like genotype and similar morphologiesand immomohistochemical staining patterns. It is also possiblethat impaired functioning or reduction of expression level ofBRCA1 gives rise to sporadic basal-like breast cancers.
3BRCA2Fanconi anemia group D1 proteinBreast cancer type 2 susceptibility proteinMutationP51587NM_000059Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. In concert with NPM1, regulates centrosome duplication.
4MAP2K4JNK-activating kinase 1, MAPK/ERK kinase 4, SAPK/ERK kinase 1, Stress-activated protein kinase kinase 1, c-Jun N-terminal kinase kinase 1 Dual-specificity mitogen-activated protein kinase kinase 4 MutationP45985 NM_003010Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
5MAP3K1MAPK/ERK kinase kinase 1Mitogen-activated protein kinase kinase kinase 1MutationQ13233 NM_005921Component of a protein kinase signal transduction cascade. Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway
6PIK3CAPhosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha, Phosphoinositide-3-kinase catalytic alpha polypeptide, Serine/threonine protein kinase PIK3CA Phosphoinositide-3-kinase catalytic alpha polypeptide Serine/threonine protein kinase PIK3CA)MutationP42336NM_006218Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS
7RB1pRb, p105-Rb, pp110Retinoblastoma-associated proteinMutationP06400NM_000321Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex By similarity. In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity
8TP53Antigen NY-CO-13, Phosphoprotein p53, Tumor suppressor p53Cellular tumor antigen p53MutationP04637 NM_000546Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.
9ERBB2Metastatic lymph node gene 19 protein, Proto-oncogene Neu, Proto-oncogene c-ErbB-2, Tyrosine kinase-type cell surface receptor HER2, p185erbB2Receptor tyrosine-protein kinase erbB-2ExpressionP04626 NM_001005862Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.
11ERBB3Proto-oncogene-like protein c-ErbB-3, Tyrosine kinase-type cell surface receptor HER3Receptor tyrosine-protein kinase erbB-3ExpressionP21860 NM_001005915EGF receptor (EGFR, ErbB) family of receptors can promote tumorigenesisand many epithelial cancers are marked by functionalactivation of ErbB family members. The ErbB familyconsists of 4 related tyrosine kinase receptors EGFR,ErbB2 (HER2/NEU), ErbB3, and ErbB4.ErbB3 is uniqueamong these because it is deficient in tyrosine kinaseactivity. However, it is readily phosphorylated uponheterodimerization with ligand-activated EGFR or withErbB2. In its fully phosphorylated state, it contains 6binding sites for phosphoinositide 3-kinases (PI3K) andtherefore constitutes one of the most potent activators ofthe AKT signaling pathway. Because the AKT pathway is intimately involved in coordinating cell proliferation, survival, metabolism, size, and angiogenesis, ErbB3represents a pivotal node in regulating these pathways.
12ERBB4Proto-oncogene-like protein c-ErbB-4, Tyrosine kinase-type cell surface receptor HER4, p180erbB4Receptor tyrosine-protein kinase erbB-4ExpressionQ15303NM_005235HER4 is known to potentially exert a tumour cell killing activity and in turn to have a favourable impact in breast cancer patients. HER4, if coexpressed to HER2, could synergistically extenuate proliferative and survival signalling.
13IGF1RInsulin-like growth factor I receptorInsulin-like growth factor 1 receptorExpressionP08069NM_000875Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. ACTIVATION OF IGF SIGNALING PATHWAY OVERCOMES INHIBITION OF HER2 SIGNALING PATHWAY
14ESR1ER-alpha, Estradiol receptor, Nuclear receptor subfamily 3 group A member 1Estrogen receptorExpressionP03372NM_000125 Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.
15ESR2Nuclear receptor subfamily 3 group A member 2Estrogen receptor betaExpressionQ92731 NM_001040275Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
16CCNE1G1/S-specific cyclin-E1ExpressionP24864NM_001238 Essential for the control of the cell cycle at the G1/S (start) transition . Trastuzumab resistant cells had an amplified region in 19q where CCNE1, the cyclin E encoding gene, resides and confirmed that these cells had cyclin E amplification/overexppresion. Cyclin E and its associated CDK2are essential forcellular progression through the G1 phase of the cell cycle andinitiation of DNA replication. On the other hand, the antiproliferativeeffects of trastuzumab are mediated by accumulation ofcells in the G1 phase, which can be accompanied by decreasedcyclin E-associated kinase activity (39). An excess of cyclin E render cells independent from trastuzumab-mediatedcell cycle arrest.cyclin E–CDK2 activity appears to becritical for both parental and trastuzumab-resistant cells, its inhibitionleads to different phenotypic outcomes. Whereas exposureto a CDK2 inhibitor moderately increased cell death inBT474 parental cells, identical treatment conditions resulted inmassive apoptosis in cyclin E overexpressing cells. Thus, theenhanced cyclin E–CDK2 kinase activity present in our trastuzumab-resistant cells, witnessed by the higher basal phosphorylationof RB, may be essential for the suppression of proapoptoticsignals. This finding opens up a window of opportunity becausecyclin E amplified HER2+ breast cancers refractory to trastuzumabmay be exquisitely sensitive to CDK2 inhibition.sO, overexpression of cyclin E and correspondingCDK2 activity is sufficient to counteract the antiproliferativeeffects of trastuzumab
17PPP1R1BDARPP-32, Dopamine- and cAMP-regulated neuronal phosphoproteinProtein phosphatase 1 regulatory subunit 1BExpressionQ9UD71 NM_001242464Inhibitor of protein-phosphatase 1. PPP1R1B effectively abrogated trastuzumab-induced apoptosis, inhibited cleavage of caspase-3, and blocked trastuzumab-induced dephosphorylation of ERBB2 and AKT proteins.
18HSPB128 kDa heat shock protein, Estrogen-regulated 24 kDa protein, Heat shock 27 kDa protein, Stress-responsive protein 27 Heat shock protein beta-1ExpressionP04792NM_001540Involved in stress resistance, actin organization and upregulation of HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.
19HSPB3Heat shock 17 kDa protein, Protein 3Heat shock protein beta-3ExpressionQ12988 NM_006308Inhibitor of actin polymerization.
20CDC37Hsp90 chaperone protein kinase-targeting subunit, p50Cdc37Hsp90 co-chaperone Cdc37ExpressionQ16543NM_007065Co-chaperone that binds to numerous kinases and promotes their interaction with the Hsp90 complex, resulting in stabilization and promotion of their activity.
21FOXM1FKHL16, HFH11, MPP2, WIN(Forkhead box protein M1)(MPM-2 reactive phosphoprotein 2)ExpressionQ08050NM_001243088FoxM1 is regulated throughout the cell cycle and altered microtubule dynamics in order to protect tumor cells from paclitaxel-induced apoptosis. FoxM1overexpression confers resistance to the HER2 monoclonal antibody Herceptin and microtubulestabilizing drug paclitaxel, both as single agents and in combination.
22ADAM10CDw156, Kuzbanian protein homolog, Mammalian disintegrin-metalloproteaseDisintegrin and metalloproteinase domain-containing protein 10ExpressionO14672 NM_001110Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. May regulate the EFNA5-EPHA3 signaling.
23ADAM17Snake venom-like protease, TNF-alpha convertase, TNF-alpha-converting enzyme, Disintegrin and metalloproteinase domain-containing protein 17ExpressionP78536 NM_003183Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Also involved in the activation of Notch pathway ADAM17 ACTIVETED PKB NEGATIVE FEEDBACK IN TRASTUZUMAB TREATMENT TO MAINTAIN THE RELEASE OF HER LIGAND TO MEDIATE THE DIMERIZATION AND ACTIVATION OF EGFR, HER3 AND HER4 ALONG WITH HER2
24EPHA2Epithelial cell kinase, Tyrosine-protein kinase receptor ECKEphrin type-A receptor 2ExpressionP29317 NM_004431Eph receptor A2 (EphA2), an Eph-family RTK. In human and murine breast carcinoma cells, EphA2 forms a complex with HER2, resulting in enhanced activation of Ras-mitogen-activated protein kinase (MAPK) and RhoA GTPase and increased cell proliferation and motility.In many reports, high EphA2 levels enhanced both intrinsic and acquired trastuzumab resistance. Elevated EphA2 in resistant cells seems to be activated by trastuzumab treatment–induced Src kinase, and activated EphA2 amplifies signaling through the phosphoinositide 3-kinase (PI3K)/Akt and MAPK pathways in resistant cells
25RAC1Cell migration-inducing gene 5 protein, Ras-like protein TC25, p21-Rac1Ras-related C3 botulinum toxin substrate 1ExpressionP63000 NM_006908Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages By similarity. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In glioma cells, promotes cell migration and invasion.
27CD44Extracellular matrix receptor III, Heparan sulfate proteoglycanHermes antigenHyaluronate receptorPhagocytic glycoprotein 1, Phagocytic glycoprotein I, GP90 lymphocyte homing/adhesion receptorHUTCH-ICD44 antigenExpressionP16070 NM_000610Receptor for hyaluronic acid (HA). Mediates cell-cell and cell-matrix interactions through its affinity for HA, and possibly also through its affinity for other ligands such as osteopontin, collagens, and matrix metalloproteinases (MMPs). Adhesion with HA plays an important role in cell migration, tumor growth and progression. Also involved in lymphocyte activation, recirculation and homing, and in hematopoiesis. Altered expression or dysfunction causes numerous pathogenic phenotypes. Great protein heterogeneity due to numerous alternative splicing and post-translational modification events.
28METHGF/SF receptorProto-oncogene c-MetScatter factor receptor, Tyrosine-protein kinase MetHepatocyte growth factor receptorExpressionP08581 NM_000245Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.
29CXCR4FB22FusinHM89LCR1Leukocyte-derived seven transmembrane domain receptor, NPYRL, Stromal cell-derived factor 1 receptorC-X-C chemokine receptor type 4ExpressionP61073NM_001008540Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus.