GRB2

GRB2（growth factor receptor bound protein 2）は、シグナル伝達に関与するアダプタータンパク質である。ヒトでは、GRB2タンパク質はGRB2遺伝子によってコードされている^[5][6]。

GRB2
PDBに登録されている構造 PDB オルソログ検索: RCSB PDBe PDBj PDBのIDコード一覧 1AZE, 1BM2, 1BMB, 1CJ1, 1FHS, 1FYR, 1GCQ, 1GFC, 1GFD, 1GHU, 1GRI, 1IO6, 1JYQ, 1JYR, 1JYU, 1QG1, 1TZE, 1X0N, 1ZFP, 2AOA, 2AOB, 2H5K, 2HUW, 2VVK, 2VWF, 2W0Z, 3C7I, 3IMD, 3IMJ, 3IN7, 3IN8, 3KFJ, 3MXC, 3MXY, 3N7Y, 3N84, 3N8M, 3OV1, 3OVE, 3S8L, 3S8N, 3S8O, 2H46, 3WA4, 4P9V, 4P9Z, 5CDW
識別子
記号	GRB2, ASH, EGFRBP-Grb3-3, MST084, MSTP084, NCKAP2, growth factor receptor bound protein 2
外部ID	OMIM: 108355 MGI: 95805 HomoloGene: 1576 GeneCards: GRB2
遺伝子の位置 (ヒト) 染色体 17番染色体 (ヒト)[1] バンド データ無し 開始点 75,318,076 bp[1] 終点 75,405,709 bp[1]
遺伝子の位置 (マウス) 染色体 11番染色体 (マウス)[2] バンド データ無し 開始点 115,534,871 bp[2] 終点 115,599,423 bp[2]
RNA発現パターン さらなる参照発現データ
遺伝子オントロジー 分子機能 • protein domain specific binding • SH3 domain binding • プロテインキナーゼ結合 • identical protein binding • neurotrophin TRKA receptor binding • protein phosphatase binding • 血漿タンパク結合 • ephrin receptor binding • insulin receptor substrate binding • epidermal growth factor receptor binding • phosphatidylinositol-4,5-bisphosphate 3-kinase activity • 1-phosphatidylinositol-3-kinase activity • phosphoprotein binding • 酵素結合 • RNA結合 • non-membrane spanning protein tyrosine kinase activity • phosphotyrosine residue binding 細胞の構成要素 • エキソソーム • 核小体 • 細胞質 • 核質 • COP9シグナロソーム • ゴルジ体 • 細胞質基質 • 細胞核 • cell-cell junction • 膜 • Grb2-EGFR complex • エンドソーム • vesicle membrane • 細胞膜 • extrinsic component of cytoplasmic side of plasma membrane • 高分子複合体 • 細胞内 生物学的プロセス • T cell costimulation • Fc-gamma receptor signaling pathway involved in phagocytosis • branching involved in labyrinthine layer morphogenesis • MAPK cascade • epidermal growth factor receptor signaling pathway • fibroblast growth factor receptor signaling pathway • insulin receptor signaling pathway • receptor internalization • 細胞間シグナル伝達 • 軸索誘導 • positive regulation of reactive oxygen species metabolic process • cellular response to ionizing radiation • Fc-epsilon receptor signaling pathway • viral process • positive regulation of actin filament polymerization • signal transduction in response to DNA damage • negative regulation of epidermal growth factor receptor signaling pathway • leukocyte migration • regulation of MAPK cascade • anatomical structure formation involved in morphogenesis • 老化 • ERBB2 signaling pathway • phosphatidylinositol phosphate biosynthetic process • phosphatidylinositol-3-phosphate biosynthetic process • protein heterooligomerization • entry of bacterium into host cell • membrane organization • 遊走 • 細胞分化 • peptidyl-tyrosine autophosphorylation • regulation of cell population proliferation • 自然免疫 • Ras protein signal transduction • interleukin-15-mediated signaling pathway • positive regulation of protein kinase B signaling • regulation of molecular function • サイトカイン媒介シグナル伝達経路 • positive regulation of Ras protein signal transduction • neurotrophin TRK receptor signaling pathway 出典:Amigo / QuickGO
オルソログ
種	ヒト	マウス
Entrez	2885	14784
Ensembl	ENSG00000177885	ENSMUSG00000059923
UniProt	P62993,J3KT38	Q60631
RefSeq (mRNA)	NM_203506 NM_002086	NM_008163 NM_001313936 NM_001313937
RefSeq (タンパク質)	NP_002077 NP_987102	NP_001300865 NP_001300866 NP_032189
場所 (UCSC)	Chr 17: 75.32 – 75.41 Mb	Chr 17: 115.53 – 115.6 Mb
PubMed検索	[3]	[4]
ウィキデータ
閲覧/編集 ヒト 閲覧/編集 マウス

GRB2は上皮成長因子受容体などの受容体に結合するタンパク質で、1つのSH2ドメインと2つのSH3ドメインを有する。2つのSH3ドメインは他のタンパク質のプロリンリッチ領域と直接的に相互作用して複合体形成へ差し向け、SH2ドメインはリン酸化されたチロシンを含む配列に結合する。GRB2遺伝子はCaenorhabditis elegansにおいてシグナル伝達経路に関与しているsem-5遺伝子と類似している。GRB2遺伝子には、異なるアイソフォームをコードする2種類の選択的スプライシングバリアントが発見されている^[7]。

機能

GRB2は複数の細胞機能に必要不可欠な役割を果たしている。GRB2の機能の阻害によって、さまざまな生物種で発生過程が損なわれ、またさまざまな細胞種で形質転換や増殖が遮断される。GRB2は上皮成長因子受容体と、Rasやその下流のキナーゼであるERK1/2とを関連づける役割が最もよく知られている。一方で、GRB2はHER2の場合には他のキナーゼAKTに対して関連づける。このように、さまざまな受容体型チロシンキナーゼのシグナルがGRB2へ収束する可能性があるものの、これらのシグナルは必ずしも同じ下流キナーゼの活性化を引き起こすためにGRB2を利用しているわけではない^[8]。

ドメイン

GRB2はSH2ドメインの両側にSH3ドメインが隣接した構成をしている^[9]。

GRB2のSH2ドメインは、受容体やアダプタータンパク質に存在するリン酸化チロシン（pY）含有モチーフに結合する。pY-X-N-X配列（Xは任意のアミノ酸）に対して選択的に結合するが、pY-(L/V)-N-(V/P)配列に対してより高い親和性で結合する^[10]。

N末端側のSH3ドメインはプロリンに富むペプチドに結合し、Rasのグアニンヌクレオチド交換因子であるSos（英語版）に結合することができる^[11]。

C末端側のSH3ドメインはP-X-X-X-Rモチーフを有するペプチドに結合し、GAB1（英語版）などのタンパク質への特異的結合を可能にしている^[12]。

相互作用

GRB2は次に挙げる因子と相互作用することが示されている。

• ADAM15（英語版）^[13]
• ABL1^[14][15]
• ALOX5^[16][17]
• BLNK（英語版）^{[18][19][20][21]}
• BCAR1（英語版）^[22][23]
• BCR^{[24][25][26][27][28][29]}
• β₂AR（英語版）^[30]
• c-Met^[31][32]
• CBLB（英語版）^[33][34][35]
• CD117^[36][37][38]
• CD22（英語版）^[39][40]
• CD28（英語版）^[41][42]
• CDKN1B^[43]
• CRK（英語版）^[44][45][46]
• CBL^{[33][47][48][49][50][51][52][53][54][55][56][57][58]}
• CSF1R（英語版）^[59]
• DCTN1（英語版）^[60]
• DNM1（英語版）^[61][62]
• DOCK1（英語版）^[63][64]
• DAG1（英語版）^[65]
• EPHA2（英語版）^[66]
• ETV6^[24]
• EGFR^{[6][67][68][69][70][71][72][73][74][75]}
• EPOR（英語版）^[36][76]
• FRS2（英語版）^{[48][77][78][79]}
• FASL^[80][81]
• GAB1（英語版）^[67][82][83]
• GAB2（英語版）^[24][84][85]
• gp130（英語版）^[86]
• G-CSF受容体（英語版）^[87]
• HER2^[69][88][89]
• HNRNPC（英語版）^[90]
• HTT^[91]
• INPP5D（英語版）^[92]
• IRS1^[93][94][95]
• ITK（英語版）^[96][97]
• JAK1（英語版）^[93][98]
• JAK2（英語版）^[93][99]
• KHDRBS1^{[50][67][100]}
• LAT（英語版）^{[101][102][103]}
• LCP2（英語版）^{[47][82][104][105][106]}
• MAP2（英語版）^[107][108]
• MAP3K1（英語版）^[109]
• MAP4K1（英語版）^{[110][111][112][113]}
• MED28（英語版）^[114]
• MST1R（英語版）^[115][116]
• MUC1（英語版）^[117]
• MAPK9（英語版）^[118][119]
• NCKIPSD（英語版）^[120][121]
• NEU3（英語版）^[122]
• PDGFRB（英語版）^{[75][123][124]}
• PIK3R1（英語版）^[125][126]
• PLCG1（英語版）^{[127][128][129]}
• PRKAR1A（英語版）^[72]
• PTK2^{[22][130][131][132][133]}
• PTPN11^{[87][124][134][135][136][137][138][139][140]}
• PTPN12（英語版）^[141]
• PTPN1（英語版）^[142][143]
• PTPN6（英語版）^{[49][135][144]}
• PTPRA（英語版）^{[145][146][147]}
• RAPGEF1（英語版）^[148][149]
• RET^[150][151]
• SH2B1（英語版）^[152][153]
• SH3KBP1（英語版）^[154][155]
• SHC1（英語版）^{[25][49][51][68][94][134][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170]}
• SOS1（英語版）^{[25][46][48][49][50][51][62][67][68][74][104][117][128][162][169][171][172][173][174][175][176]}
• Src^[49][177]
• SYK（英語版）^[49][135]
• TNK2（英語版）^[156][178]
• TrkA（英語版）^[179][180]
• VAV1（英語版）^{[86][171][181][182]}
• VAV2（英語版）^[68][88]
• VAV3（英語版）^[68][183]
• WASP（英語版）^[184][185]

出典

1. GRCh38: Ensembl release 89: ENSG00000177885 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000059923 - Ensembl, May 2017
3. Human PubMed Reference:
4. Mouse PubMed Reference:
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6. “The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling”. Cell 70 (3): 431–42. (Aug 1992). doi:10.1016/0092-8674(92)90167-B. PMID 1322798.
7. “Entrez Gene: GRB2 growth factor receptor-bound protein 2”. 2024年9月29日閲覧。
8. Tari, A. M.; Lopez-Berestein, G. (2001-10). “GRB2: a pivotal protein in signal transduction”. Seminars in Oncology 28 (5 Suppl 16): 142–147. doi:10.1016/s0093-7754(01)90291-x. ISSN 0093-7754. PMID 11706405. https://pubmed.ncbi.nlm.nih.gov/11706405.
9. Yablonski, Deborah (2019). “Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses”. Frontiers in Immunology 10: 1704. doi:10.3389/fimmu.2019.01704. ISSN 1664-3224. PMC 6669380. PMID 31402911. https://pubmed.ncbi.nlm.nih.gov/31402911.
10. Higo, Kunitake; Ikura, Teikichi; Oda, Masayuki; Morii, Hisayuki; Takahashi, Jun; Abe, Ryo; Ito, Nobutoshi (2013). “High resolution crystal structure of the Grb2 SH2 domain with a phosphopeptide derived from CD28”. PloS One 8 (9): e74482. doi:10.1371/journal.pone.0074482. ISSN 1932-6203. PMC 3787023. PMID 24098653. https://pubmed.ncbi.nlm.nih.gov/24098653.
11. Ogura, Kenji; Okamura, Hideyasu (2013-10-09). “Conformational change of Sos-derived proline-rich peptide upon binding Grb2 N-terminal SH3 domain probed by NMR”. Scientific Reports 3: 2913. doi:10.1038/srep02913. ISSN 2045-2322. PMC 6505672. PMID 24105423. https://pubmed.ncbi.nlm.nih.gov/24105423.
12. Lock, L. S.; Royal, I.; Naujokas, M. A.; Park, M. (2000-10-06). “Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases”. The Journal of Biological Chemistry 275 (40): 31536–31545. doi:10.1074/jbc.M003597200. ISSN 0021-9258. PMID 10913131. https://pubmed.ncbi.nlm.nih.gov/10913131.
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14. “The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr”. The Journal of Biological Chemistry 272 (52): 33260–70. (Dec 1997). doi:10.1074/jbc.272.52.33260. PMID 9407116.
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16. “Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2”. Analytical Biochemistry 230 (1): 108–14. (Sep 1995). doi:10.1006/abio.1995.1444. PMID 8585605.
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20. “BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking”. European Journal of Immunology 30 (5): 1326–30. (May 2000). doi:10.1002/(sici)1521-4141(200005)30:5<1326::aid-immu1326>3.0.co;2-q. PMID 10820378.
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24. “A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase”. Molecular and Cellular Biology 24 (11): 4685–95. (Jun 2004). doi:10.1128/MCB.24.11.4685-4695.2004. PMC 416425. PMID 15143164. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC416425/.
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26. “The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase”. Blood 96 (2): 664–70. (Jul 2000). doi:10.1182/blood.V96.2.664. PMID 10887132. http://www.escholarship.org/uc/item/2pv2423x.
27. “The SH2-containing adapter protein GRB10 interacts with BCR-ABL”. Oncogene 17 (8): 941–8. (Aug 1998). doi:10.1038/sj.onc.1202024. PMID 9747873.
28. “Bcr phosphorylated on tyrosine 177 binds Grb2”. Oncogene 14 (19): 2367–72. (May 1997). doi:10.1038/sj.onc.1201053. PMID 9178913.
29. “Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS”. Molecular and Cellular Biology 15 (2): 835–42. (Feb 1995). doi:10.1128/mcb.15.2.835. PMC 231961. PMID 7529874. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC231961/.
30. “Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350”. The Journal of Biological Chemistry 273 (49): 33035–41. (Dec 1998). doi:10.1074/jbc.273.49.33035. PMID 9830057.
31. “Specific uncoupling of GRB2 from the Met receptor. Differential effects on transformation and motility”. The Journal of Biological Chemistry 271 (24): 14119–23. (Jun 1996). doi:10.1074/jbc.271.24.14119. PMID 8662889.
32. “Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways”. Investigative Ophthalmology & Visual Science 39 (8): 1329–38. (Jul 1998). PMID 9660480.
33. “cbl-b inhibits epidermal growth factor receptor signaling”. Oncogene 18 (10): 1855–66. (Mar 1999). doi:10.1038/sj.onc.1202499. PMID 10086340.
34. “The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells”. The Journal of Biological Chemistry 273 (24): 14962–7. (Jun 1998). doi:10.1074/jbc.273.24.14962. PMID 9614102.
35. “Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation”. Oncogene 18 (5): 1147–56. (Feb 1999). doi:10.1038/sj.onc.1202411. PMID 10022120.
36. “Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway”. The Journal of Biological Chemistry 271 (21): 12129–32. (May 1996). doi:10.1074/jbc.271.21.12129. PMID 8647802.
37. “Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation”. The EMBO Journal 18 (4): 904–15. (Feb 1999). doi:10.1093/emboj/18.4.904. PMC 1171183. PMID 10022833. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1171183/.
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39. “CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux”. The Journal of Biological Chemistry 275 (23): 17420–7. (Jun 2000). doi:10.1074/jbc.M001892200. PMID 10748054.
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47. “Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages”. Journal of Leukocyte Biology 65 (4): 523–34. (Apr 1999). doi:10.1002/jlb.65.4.523. PMID 10204582.
48. “FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl”. Proceedings of the National Academy of Sciences of the United States of America 99 (10): 6684–9. (May 2002). Bibcode: 2002PNAS...99.6684W. doi:10.1073/pnas.052138899. PMC 124463. PMID 11997436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC124463/.
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50. “Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc”. Oncogene 17 (24): 3073–82. (Dec 1998). doi:10.1038/sj.onc.1202337. PMID 9872323.
51. “High affinity IgG receptor activation of Src family kinases is required for modulation of the Shc-Grb2-Sos complex and the downstream activation of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase”. Journal of Immunology 163 (11): 6023–34. (Dec 1999). doi:10.4049/jimmunol.163.11.6023. PMID 10570290.
52. “Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase”. Oncogene 14 (18): 2217–28. (May 1997). doi:10.1038/sj.onc.1201049. PMID 9174058.
53. “A c-Cbl yeast two hybrid screen reveals interactions with 14-3-3 isoforms and cytoskeletal components”. Biochemical and Biophysical Research Communications 240 (1): 46–50. (Nov 1997). doi:10.1006/bbrc.1997.7608. PMID 9367879.
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関連文献

• “Interaction between the nicotinic acetylcholine receptor and Grb2. Implications for signaling at the neuromuscular junction”. Annals of the New York Academy of Sciences 841 (1): 17–27. (May 1998). Bibcode: 1998NYASA.841...17C. doi:10.1111/j.1749-6632.1998.tb10907.x. PMID 9668219.
• “Waltzing with WASP”. Trends in Cell Biology 9 (1): 15–9. (Jan 1999). doi:10.1016/S0962-8924(98)01411-1. PMID 10087612.
• “Wiskott-Aldrich syndrome protein, WASP”. The International Journal of Biochemistry & Cell Biology 31 (3–4): 383–7. (1999). doi:10.1016/S1357-2725(98)00118-6. PMID 10224664.
• “Signaling through focal adhesion kinase”. Progress in Biophysics and Molecular Biology 71 (3–4): 435–78. (1999). doi:10.1016/S0079-6107(98)00052-2. PMID 10354709. http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-37555.
• “[Design of new anti-tumor agents interrupting deregulated signaling pathways induced by tyrosine kinase proteins. Inhibition of protein-protein interaction involving Grb2]”. Journal de la Société de Biologie 198 (2): 133–7. (2004). doi:10.1051/jbio/2004198020133. PMID 15368963.

関連項目

• MAPK/ERK経路（英語版）

外部リンク

• GRB2 Adaptor Protein - MeSH・アメリカ国立医学図書館・生命科学用語シソーラス（英語）
• The Grb2 protein page on The SH2 Website
• GeneCards entry for Grb2
• Human Protein Resource Database entry for Grb2
• Grb2 information on iHOP
• GRB2 Info with links in the Cell Migration Gateway Archived December 11, 2014, at the Wayback Machine.