ERBB3

Il recettore tirosin chinasico erbB-3 è un enzima che nell'uomo viene codificato dal gene ERBB3^[1].

Struttura proteica codificata da ERBB3

Pattern di espressione ad RNA del gene ERBB3

Questo gene codifica per una porzione del recettore del fattore di crescita dell'epidermide (Epidermal Growth Factor Receptor, EGFR) appartenente alla famiglia dei recettori tirosin chinasici. Questa proteina di membrana possiede neurodominio di interazione, ma non un dominio di attivazione chinasi dipendente. Risulta quindi possibile l'associazione con un ligando, ma non la trasmissione del segnale all'interno della cellula attraverso le reazioni di fosforilazione delle proteine segnale. Tuttavia, erbB-3 risulta in grado di costituire eterodimeri associandosi ad altri membri della famiglia del recettore EGF i quali possiedono domini di attivazione chinasi dipendente. L'eterodimerizzazione consente l'attivazione di reazioni a cascata all'interno della cellula che portano alla proliferazione cellulare o alla differenziazione.

L'eventuale amplificazione del gene ERBB3 o la sua sovraespressione, portano all'accumulo della proteina erbB-3, tale accumulo di prodotto proteico è stato riscontrato in numerosi tumori, tra cui quello alla prostata, alla vescica e nei tumori al seno. L'RNA del gene può essere sottoposto a splicing alternativo, ciò consente la codifica di diverse varianti, le quali una volta tradotte danno origine a diverse isoforme proteiche. Una particolare isoforma è priva della regione intermembranale e viene quindi secreta all'esterno della cellula; Tale isoforma consente la modulazione dell'attività dell'isoforma legata alla membrana. Altre varianti di splicing sono state identificate, ma non sono state completamente caratterizzate^[2].

Si ritiene che ERBB3, se attivato, diventi un substrato per la dimerizzazione e fosforilazione successiva di: ErbB1, ErbB2 e ERBB4.

Come molti dei recettori tirosin chinasici, ERBB3 è attivato dal ligando extracellulare. Ligandi noti in grado di legarsi a ERBB3 sono le Neuregulin.

Interazioni

Il recetterore erbB-3 è in grado di interagire con: Neuregulin 1,^[3]^[4]^[5] PA2G4,^[6]^[7] PIK3R1^[8]^[9] e RGS4.^[10]

Note

^ Sequenza e posizione: Human chr12:54,760,159-54,783,395 - UCSC Genome Browser v273
^ Entrez Gene: ERBB3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian), su ncbi.nlm.nih.gov.
^ E Singer, Landgraf R, Horan T, Slamon D, Eisenberg D, Identification of a heregulin binding site in HER3 extracellular domain, in J. Biol. Chem., vol. 276, n. 47, United States, novembre 2001, pp. 44266–74, DOI:10.1074/jbc.M105428200, ISSN 0021-9258 (WC · ACNP), PMID 11555649.
^ T Horan, Wen J, Arakawa T, Liu N, Brankow D, Hu S, Ratzkin B, Philo J S, Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3, in J. Biol. Chem., vol. 270, n. 41, UNITED STATES, ottobre 1995, pp. 24604–8, DOI:10.1074/jbc.270.41.24604, ISSN 0021-9258 (WC · ACNP), PMID 7592681.
^ K L Carraway, Weber J L, Unger M J, Ledesma J, Yu N, Gassmann M, Lai C, Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases, in Nature, vol. 387, n. 6632, ENGLAND, maggio. 1997, pp. 512–6, DOI:10.1038/387512a0, ISSN 0028-0836 (WC · ACNP), PMID 9168115.
^ T J Lessor, Hamburger A W, Regulation of the ErbB3 binding protein Ebp1 by protein kinase C, in Mol. Cell. Endocrinol., vol. 175, 1–2, Ireland, aprile 2001, pp. 185–91, DOI:10.1016/S0303-7207(01)00387-2, ISSN 0303-7207 (WC · ACNP), PMID 11325528.
^ J Y Yoo, Wang X W, Rishi A K, Lessor T, Xia X M, Gustafson T A, Hamburger A W, Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin, in Br. J. Cancer, vol. 82, n. 3, SCOTLAND, febbraio 2000, pp. 683–90, DOI:10.1054/bjoc.1999.0981, ISSN 0007-0920 (WC · ACNP), PMC 2363329, PMID 10682683.
^ N J Hellyer, Kim M S, Koland J G, Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor, in J. Biol. Chem., vol. 276, n. 45, United States, novembre 2001, pp. 42153–61, DOI:10.1074/jbc.M102079200, ISSN 0021-9258 (WC · ACNP), PMID 11546794.
^ J Lin, Adam R M, Santiestevan E, Freeman M R, The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells, in Cancer Res., vol. 59, n. 12, UNITED STATES, giugno 1999, pp. 2891–7, ISSN 0008-5472 (WC · ACNP), PMID 10383151.
^ Safia Thaminy, Auerbach Daniel, Arnoldo Anthony, Stagljar Igor, Identification of novel ErbB3-interacting factors using the split-ubiquitin membrane yeast two-hybrid system, in Genome Res., vol. 13, n. 7, United States, luglio 2003, pp. 1744–53, DOI:10.1101/gr.1276503, ISSN 1088-9051 (WC · ACNP), PMC 403748, PMID 12840049.

Bibliografia

Corfas G, Roy K, Buxbaum JD, Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia, in Nat. Neurosci., vol. 7, n. 6, 2004, pp. 575–80, DOI:10.1038/nn1258, PMID 15162166.
Plowman GD, Whitney GS, Neubauer MG, et al., Molecular cloning and expression of an additional epidermal growth factor receptor-related gene, in Proc. Natl. Acad. Sci. U.S.A., vol. 87, n. 13, 1990, pp. 4905–9, DOI:10.1073/pnas.87.13.4905, PMC 54229, PMID 2164210.
Kraus MH, Issing W, Miki T, et al., Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors, in Proc. Natl. Acad. Sci. U.S.A., vol. 86, n. 23, 1990, pp. 9193–7, DOI:10.1073/pnas.86.23.9193, PMC 298460, PMID 2687875.
Alimandi M, Romano A, Curia MC, et al., Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas, in Oncogene, vol. 10, n. 9, 1995, pp. 1813–21, PMID 7538656.
Wallasch C, Weiss FU, Niederfellner G, et al., Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3, in EMBO J., vol. 14, n. 17, 1995, pp. 4267–75, PMC 394510, PMID 7556068.
Horan T, Wen J, Arakawa T, et al., Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3, in J. Biol. Chem., vol. 270, n. 41, 1995, pp. 24604–8, DOI:10.1074/jbc.270.41.24604, PMID 7592681.
Shintani S, Funayama T, Yoshihama Y, et al., Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma, in Cancer Lett., vol. 95, 1–2, 1995, pp. 79–83, DOI:10.1016/0304-3835(95)03866-U, PMID 7656248.
Katoh M, Yazaki Y, Sugimura T, Terada M, c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase, in Biochem. Biophys. Res. Commun., vol. 192, n. 3, 1993, pp. 1189–97, DOI:10.1006/bbrc.1993.1542, PMID 7685162.
Culouscou JM, Plowman GD, Carlton GW, et al., Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor, in J. Biol. Chem., vol. 268, n. 25, 1993, pp. 18407–10, PMID 7689552.
Zelada-Hedman M, Werer G, Collins P, et al., High expression of the EGFR in fibroadenomas compared to breast carcinomas, in Anticancer Res., vol. 14, 5A, 1995, pp. 1679–88, PMID 7847801.
Carraway KL, Sliwkowski MX, Akita R, et al., The erbB3 gene product is a receptor for heregulin, in J. Biol. Chem., vol. 269, n. 19, 1994, pp. 14303–6, PMID 8188716.
Shintani S, Funayama T, Yoshihama Y, et al., Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study, in Anticancer Res., vol. 15, 6B, 1996, pp. 2623–6, PMID 8669836.
Chang H, Riese DJ, Gilbert W, et al., Ligands for ErbB-family receptors encoded by a neuregulin-like gene, in Nature, vol. 387, n. 6632, 1997, pp. 509–12, DOI:10.1038/387509a0, PMID 9168114.
Carraway KL, Weber JL, Unger MJ, et al., Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases, in Nature, vol. 387, n. 6632, 1997, pp. 512–6, DOI:10.1038/387512a0, PMID 9168115.
Fiddes RJ, Campbell DH, Janes PW, et al., Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3, in J. Biol. Chem., vol. 273, n. 13, 1998, pp. 7717–24, DOI:10.1074/jbc.273.13.7717, PMID 9516479.
Jones JT, Ballinger MD, Pisacane PI, et al., Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis, in J. Biol. Chem., vol. 273, n. 19, 1998, pp. 11667–74, DOI:10.1074/jbc.273.19.11667, PMID 9565587.
Lee H, Maihle NJ, Isolation and characterization of four alternate c-erbB3 transcripts expressed in ovarian carcinoma-derived cell lines and normal human tissues, in Oncogene, vol. 16, n. 25, 1998, pp. 3243–52, DOI:10.1038/sj.onc.1201866, PMID 9681822.
Vijapurkar U, Cheng K, Koland JG, Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase, in J. Biol. Chem., vol. 273, n. 33, 1998, pp. 20996–1002, DOI:10.1074/jbc.273.33.20996, PMID 9694850.
Yoo JY, Hamburger AW, Interaction of the p23/p198 protein with ErbB-3, in Gene, vol. 229, 1–2, 1999, pp. 215–21, DOI:10.1016/S0378-1119(98)00604-0, PMID 10095121.
Lin J, Adam RM, Santiestevan E, Freeman MR, The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells, in Cancer Res., vol. 59, n. 12, 1999, pp. 2891–7, PMID 10383151.

V · D · M

Marker tumorali

Ematici

Linfoma	Neprilisina
Linfosarcoma	CD3 · CD79a

Endocrini

Tumore della tiroide	Tireoglobulina · Carcinoma midollare della tiroide (Calcitonina, Antigene carcino-embrionario)
Feocromocitoma	Normetanefrina · Enolasi 2
Tumori neuroendocrini	Sinaptofisina · Cromogranina A
Neuroblastoma	Acido omovanilico

Sistema nervoso

Tumore cerebrale	PCNA
Astrocitoma	Glial fibrillary acidic protein

Cardiovascolare/
Respiratorio

Tumore del polmone	Antigene carcino-embrionario · Enolasi 2 · Fattore autocrino di motilità
Emangiosarcoma (endotelio)	Fattore VIII

Digerente

Cancro del colon-retto	CA19-9 · Antigene carcino-embrionario
Carcinoma del pancreas	CA19-9 · Antigene carcino-embrionario · CA 242 · CA 72-4
Carcinoma epatocellulare	Alfa-feto proteina/AFP-L3

Riproduttivo/
urinario/
mammella

Carcinoma ovarico	CA-125 · CD30
Tumore del testicolo	β-HCG · Alfa-feto proteina/AFP-L3 · CD30
Carcinoma della prostata	PSA · Fosfatasi acida prostatica (PAP) · Carbossipeptidasi II · Recettore erbB-3 · Early prostate cancer antigen-2 · SPINK1 · GOLM1 · PCA3
Tumori a cellule germinali	β-HCG · Alfa-feto proteina · NANOG
Cancro della vescica	Recettore erbB-3 · NMP22
Cancro della mammella	CA 15-3 · Recettore erbB-2 · Recettore erbB-3 · Catepsina D

Istologia generale

Sarcoma	Vimentina
Carcinoma (epitelio)	Citocheratina

Altri

Melanoma	S-100 (biologia) · Melanoma inhibitory activity
Rabdomiosarcoma	Desmina

Nota: Sono tutti peptidi eccetto la normetanefrina e il PCA3.

V · D · M Genetica
Materiale genetico	Nucleotidi · Basi azotate · Acidi nucleici (DNA · RNA) · Cromosomi · Genoma
Concetti chiave	Gene · Codice genetico · Allele · Locus · Ereditarietà genetica · Diversità genetica · Mutazione genetica · Variabilità genetica
Campi della genetica	Genetica formale · Genetica molecolare · Genetica delle popolazioni · Genomica · Genetica umana · Epigenetica
Genetisti	Gregor Mendel · Thomas Hunt Morgan · Ronald Fisher · Frederick Griffith · Erwin Chargaff · Barbara McClintock · James Watson · Francis Crick · Rosalind Franklin · Alec Jeffreys

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