利用汤森路透科技集团的基本科学指标库（Essential Science Indicators）2004－2010间的高被引论文及其同被引聚类分析，通过同被引而密切关联的相关论文聚类形成若干个科学研究领域，由此绘制科学文献所反映的科学研究结构地图， 讨论科学发展的基本格局。通过研究和揭示科学结构及其演化，为各领域研究提供一种思考问题、发现潜在交叉学科、 “热点”领域。 /******************************************************************/ 第一部分： RA 10 的基本信息 /******************************************************************/ RA ID: 10 RA 的名称 雷帕霉素靶蛋白 (mTOR) 、磷酸肌醇 3 激酶 (pi3k) 信号通路与疾病发生的关系 RA 的关键词 mammalian target; pik3ca gene; protects against age- and diet-induced obesity while enhancing insulin sensitivity; pathway activation through a pi3k-dependent feedback loop in human cancer; rictor-mtor complex integrity and regulates akt phosphorylation and substrate specificity; mapk pathway activation through a pi3k-dependent feedback loop in human; sin1/mip1 maintains rictor-mtor complex integrity and regulates akt phosphorylation and; s6k1 protects against age- and diet-induced obesity while enhancing insulin; maintains rictor-mtor complex integrity and regulates akt phosphorylation and substrate; ras/erk signaling promotes site-specific ribosomal protein s6 phosphorylation via rsk 包含 RF 数 (Hot RF 数 ) 核心论文数 被引用篇数 总被引次数 平均出版年 9(4) 74 3792 8792 2006.7 该 RA 中包含 RF 的图谱 核糖体蛋白 S6 激酶磷酸化的调节作用 mTORC1 与 mTORC2 、氨基酸对 mTOR 的调控机制、 mTOR 对 akt/makp 信号通路的调节 RA 概述 雷帕霉素（ Rapamycin ）自 20 世纪 70 年代开发出来便经常作为免疫抑制剂用于器官移植，以减缓器官移植手术后的免疫排斥反应，特别是肾移植。雷帕霉素的涂层支架已为成千上万的冠心病患者解决了冠脉支架植入后的再狭窄问题，此外，新近发现雷帕霉素相关产品还是许多癌症治疗的重要靶向药物的选择。雷帕霉素靶蛋白（ mTOR ）作为细胞内激酶，是高分子量丝氨酸 - 苏氨酸激酶、磷酸肌醇 3- 激酶 (PI3K) 相关激酶 (PIKK) 的家族成员。近几年的研究发现 mTOR 传导通路的异常也可以诱发许多疾病。 mTOR 信号通路在神经疾病和抗衰老、炎症性疾病、纤维化疾病、肺动脉高压等诸多领域研究活跃，具有无限的市场应用前景。而对 mTOR 进行抑制便成为治疗与该通路密切相关的肿瘤包括肾癌、淋巴瘤、肺癌、肝癌、乳腺癌、神经内分泌癌和胃癌等的靶点所在。 /******************************************************************/ 第二部分： RA 10 包含的 9 个 RF 的基本信息 /******************************************************************/ RF ID: 6247 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 25 1434 3625 2007.5 Yes RF 的关键词 mtor-mediated translational control molecular mechanisms; mtor complex 2 (mtorc2) controls hydrophobic motif phosphorylation; intact mtor signaling complex 2; pras40 regulates mtorc1 kinase activity; mammalian tor complex 2 controls RF ID: 6714 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 20 987 2012 2007.3 No RF 的关键词 mtor/phosphatidylinositol 3-kinase inhibitor nvp-bez235 lapatinib resistance reversal; vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug; pi 3-kinase p110 beta RF ID: 8254 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 11 900 2120 2005.5 No RF 的关键词 oncogenic pi3k alpha mutations; phosphatidylinositol 3-kinase mutations identified; human breast cancers; human p110 alpha/p85 alpha complex elucidates; pik3ca mutations correlate RF ID: 11354 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 5 387 817 2005.0 No RF 的关键词 amino acid mtor/raptor signaling class-3 phosphatidylinosital 30h-kinase mediation; nutrient-regulated lipid kinase required; mammalian target; amino acid sufficiency; p70 s6 kinase RF ID: 13303 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 3 505 849 2004.0 No RF 的关键词 tsc/rheb/mtor/s6k cassette inappropriate activation induces irs1/2 depletion-insulin resistance-cell survival deficiencies; enhancing insulin sensitivity; insulin resistance; tsc1-2 tumor suppressor controls insulin-p13k signaling RF ID: 14863 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 3 315 405 2005.6 No RF 的关键词 ras/erk signaling; site-specific ribosomal protein s6 phosphorylation; mitogen-activated protein kinase-dependent s6 kinase pathway; protein synthesis; rapamycin-sensitive 5 ''-terminal oligopyrimidine mrna translation RF ID: 9782 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 3 395 574 2006.0 Yes RF 的关键词 mtor inhibition induces upstream receptor tyrosine kinase signaling; rapamycin induces feedback activation; akt signaling; rapamycin inhibition; activates akt RF ID: 7986 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 2 72 120 2008.0 Yes RF 的关键词 erk mapk signaling; hormone-refractory prostate cancer; mapk pathway activation; human cancer; pi3k-dependent feedback loop; preclinical mouse model RF ID: 12550 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 2 70 108 2008.0 Yes RF 的关键词 oncogenic cellular transformation; class ipi3k; pi3k/akt pathway; cancer; drug discovery /******************************************************************/ 第三部分： 9 个 RF 的核心论文详细列表 /******************************************************************/ RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 6247 25 1434 3625 2007.5 Yes RF 的关键词 mtor-mediated translational control molecular mechanisms; mtor complex 2 (mtorc2) controls hydrophobic motif phosphorylation; intact mtor signaling complex 2; pras40 regulates mtorc1 kinase activity; mammalian tor complex 2 controls 论文题目 被引 年份 刊名 第一作者 第一机构、国家 phosphorylation and regulation of akt/pkb by the rictor-mtor complex 1007 2005 SCIENCE SARBASSOV DD MIT, USA rictor, a novel binding partner of mtor, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton 457 2004 CURR BIOL SARBASSOV DD MIT, USA prolonged rapamycin treatment inhibits mtorc2 assembly and akt/pkb 348 2006 MOL CELL SARBASSOV DD Whitehead Inst Biomed Res, USA mammalian tor complex 2 controls the actin cytoskeleton and is rapamycin insensitive 315 2004 NAT CELL BIOL JACINTO E Univ Basel, Switzerland sin1/mip1 maintains rictor-mtor complex integrity and regulates akt phosphorylation and substrate specificity 190 2006 CELL JACINTO E Univ Texas, USA mtor center dot rictor is the ser(473) kinase for akt/protein kinase b in 3t3-l1 adipocytes 174 2005 J BIOL CHEM HRESKO RC Washington Univ, USA ablation in mice of the mtorc components raptor, rictor, or mlst8 reveals that mtorc2 is required for signaling to akt-foxo and pkc alpha but not s6k1 164 2006 DEV CELL GUERTIN DA MIT, USA pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase 141 2007 MOL CELL SANCAK Y MIT, USA ampk phosphorylation of raptor mediates a metabolic checkpoint 130 2008 MOL CELL GWINN DM Salk Inst Biol Studies, USA insulin signalling to mtor mediated by the akt/pkb substrate pras40 118 2007 NAT CELL BIOL VANDER HAAR E Univ Minnesota, USA the rag gtpases bind raptor and mediate amino acid signaling to mtorc1 114 2008 SCIENCE SANCAK Y MIT, USA msin1 is necessary for akt/pkb phosphorylation, and its isoforms define three distinct mtorc2s 93 2006 CURR BIOL FRIAS MA MIT, USA regulation of torc1 by rag gtpases in nutrient response 66 2008 NAT CELL BIOL KIM E Univ Calif San Diego, USA pras40 regulates mtorc1 kinase activity by functioning as a direct inhibitor of substrate binding 63 2007 J BIOL CHEM WANG LF Univ Virginia Hlth Syst, USA active-site inhibitors of mtor target rapamycin-resistant outputs of mtorc1 and mtorc2 51 2009 PLOS BIOL FELDMAN ME Univ Calif San Francisco, USA mtor complex 2 (mtorc2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (sgk1) 43 2008 BIOCHEM J GARCIA-MARTINEZ JM Univ Dundee, Scotland molecular mechanisms of mtor-mediated translational control 41 2009 NAT REV MOL CELL BIOL MA XJM Genentech Inc, USA mtor complex 2 is required for the development of prostate cancer induced by pten loss in mice 24 2009 CANCER CELL GUERTIN DA Whitehead Inst Biomed Res, USA biochemical, cellular, and in vivo activity of novel atp-competitive and selective inhibitors of the mammalian target of rapamycin 21 2009 CANCER RES YU K Wyeth Res, USA ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mtor) 20 2009 BIOCHEM J GARCIA-MARTINEZ JM Univ Dundee, Scotland torc-specific phosphorylation of mammalian target of rapamycin (mtor): phospho-ser(2481) is a marker for intact mtor signaling complex 2 15 2009 CANCER RES COPP J Salk Inst Biol Studies, USA rictor/torc2 regulates caenorhabditis elegans fat storage, body size, and development through sgk-1 15 2009 PLOS BIOL JONES KT Univ Calif San Francisco, USA the pharmacology of mtor inhibition 7 2009 SCI SIGNAL GUERTIN DA Nine Cambridge Ctr, USA differential requirement of mtor in postmitotic tissues and tumorigenesis 4 2009 SCI SIGNAL NARDELLA C Harvard Univ, USA characterization of the intrinsic and tsc2-gap-regulated gtpase activity of rheb by real-time nmr 4 2009 SCI SIGNAL MARSHALL CB Univ Hlth Network, Canada RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 6714 20 987 2012 2007.3 No RF 的关键词 mtor/phosphatidylinositol 3-kinase inhibitor nvp-bez235 lapatinib resistance reversal; vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug; pi 3-kinase p110 beta 论文题目 被引 年份 刊名 第一作者 第一机构、国家 pten activation contributes to tumor inhibition by trastuzumab, and loss of pten predicts trastuzumab resistance in patients 394 2004 CANCER CELL NAGATA Y Univ Texas, USA a pharmacological map of the pi3-k family defines a role for p110 alpha in insulin signaling 253 2006 CELL KNIGHT ZA Univ Calif San Francisco, USA a dual pi3 kinase/mtor inhibitor reveals emergent efficacy in glioma 190 2006 CANCER CELL FAN QW Univ Calif San Francisco, USA a functional genetic approach identifies the pi3k pathway as a major determinant of trastuzumab resistance in breast cancer 155 2007 CANCER CELL BERNS K Netherlands Canc Inst, Netherlands insulin-like growth factor-i receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells 144 2005 CANCER RES NAHTA R Univ Texas, USA pi 3-kinase p110 beta: a new target for antithrombotic therapy 137 2005 NATURE MED JACKSON SP Monash Univ, Australia critical role for the p110 alpha phosphoinositide-3-oh kinase in growth and metabolic regulation 101 2006 NATURE FOUKAS LC Ludwig Inst Canc Res, England identification and characterization of nvp-bez235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity 99 2008 MOL CANCER THER MAIRA SM Novartis Pharma AG, Switzerland pharmacologic characterization of a potent inhibitor of class i phosphatidylinositide 3-kinases 86 2007 CANCER RES RAYNAUD FI Inst Canc Res, England effective use of pi3k and mek inhibitors to treat mutant kras g12d and pik3ca h1047r murine lung cancers 70 2008 NATURE MED ENGELMAN JA Beth Israel Hosp, USA essential roles of pi(3)k-p110 beta in cell growth, metabolism and tumorigenesis 61 2008 NATURE JIA SD Dana Farber Canc Inst, USA a vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, sf1126, with antitumor and antiangiogenic activity 50 2008 CANCER RES GARLICH JR Aflac Canc Ctr Blood Disorders Serv, USA nvp-bez235, a dual pi3k/mtor inhibitor, prevents pi3k signaling and inhibits the growth of cancer cells with activating pi3k mutations 50 2008 CANCER RES SERRA V Vall Hebron Univ Hosp, Spain the identification of 2-(1h-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno pyrimidine (gdc-0941) as a potent, selective, orally bioavailable inhibitor of class ipi3 kinase for the treatment of cancer 50 2008 J MED CHEM FOLKES AJ Piramed Pharma, England angiogenesis selectively requires the p110 alpha isoform of pi3k to control endothelial cell migration 49 2008 NATURE GRAUPERA M Canc Res UK London Res Inst, England the p110 beta isoform of phosphoinositide 3-kinase signals downstream of g protein-coupled receptors and is functionally redundant with p110 gamma 45 2008 PROC NAT ACAD SCI USA GUILLERMET-GUIBERT J Queen Mary Univ London, England phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mtor/phosphatidylinositol 3-kinase inhibitor nvp-bez235 35 2008 CANCER RES EICHHORN PJA Vall Hebron Univ Hosp, Spain mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor px-866 whereas oncogenic ras is a dominant predictor for resistance 16 2009 CANCER RES IHLE NT MD Anderson Canc Ctr, USA akt-independent signaling downstream of oncogenic pik3ca mutations in human cancer 14 2009 CANCER CELL VASUDEVAN KM Harvard Univ, USA breast tumor cells with pi3k mutation or her2 amplification are selectively addicted to akt signaling 13 2008 PLOS ONE SHE QB Mem Sloan Kettering Canc Ctr, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 8254 11 900 2120 2005.5 No RF 的关键词 oncogenic pi3k alpha mutations; phosphatidylinositol 3-kinase mutations identified; human breast cancers; human p110 alpha/p85 alpha complex elucidates; pik3ca mutations correlate 论文题目 被引 年份 刊名 第一作者 第一机构、国家 high frequency of mutations of the pik3ca gene in human cancers 687 2004 SCIENCE SAMUELS Y Johns Hopkins Univ, USA mutation of the pik3ca gene in ovarian and breast cancer 245 2004 CANCER RES CAMPBELL IG Peter MacCallum Canc Ctr, Australia phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic 225 2005 PROC NAT ACAD SCI USA KANG SY Scripps Res Inst, USA mutant pik3ca promotes cell growth and invasion of human cancer cells 208 2005 CANCER CELL SAMUELS Y Johns Hopkins Univ, USA pik3ca mutations correlate with hormone receptors, node metastasis, and erbb2, and are mutually exclusive with pten loss in human breast carcinoma 190 2005 CANCER RES SAAL LH Columbia Univ Coll Phys Surg, USA the pik3ca gene is mutated with high frequency in human breast cancers 161 2004 CANCER BIOL THER BACHMAN KE Johns Hopkins Univ, USA pik3ca gene is frequently mutated in breast carcinomas and hepatocellular carcinomas 146 2005 ONCOGENE LEE JW Catholic Univ Korea, South Korea cancer-specific mutations in pik3ca are oncogenic in vivo 95 2006 PROC NAT ACAD SCI USA BADER AG Scripps Res Inst, USA the structure of a human p110 alpha/p85 alpha complex elucidates the effects of oncogenic pi3k alpha mutations 68 2007 SCIENCE HUANG CH Johns Hopkins Kimmel Canc Ctr, USA mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit 61 2007 SCIENCE MILED N MRC, England helical domain and kinase domain mutations in p110 alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms 34 2008 PROC NAT ACAD SCI USA ZHAO L Scripps Res Inst, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 11354 5 387 817 2005.0 No RF 的关键词 amino acid mtor/raptor signaling class-3 phosphatidylinosital 30h-kinase mediation; nutrient-regulated lipid kinase required; mammalian target; amino acid sufficiency; p70 s6 kinase 论文题目 被引 年份 刊名 第一作者 第一机构、国家 amino acids mediate mtor/raptor signaling through activation of class 3 phosphatidylinositol 30h-kinase 217 2005 PROC NAT ACAD SCI USA NOBUKUNI T Univ Utrecht, Netherlands rheb binds and regulates the mtor kinase 198 2005 CURR BIOL LONG X Massachusetts Gen Hosp, USA hvps34 is a nutrient-regulated lipid kinase required for activation of p70 s6 kinase 177 2005 J BIOL CHEM BYFIELD MP Albert Einstein Coll Med, USA the tuberous sclerosis protein tsc2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses 115 2005 J BIOL CHEM SMITH EM Univ British Columbia, Canada rheb binding to mammalian target of rapamycin (mtor) is regulated by amino acid sufficiency 110 2005 J BIOL CHEM LONG XM Harvard Univ, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 13303 3 505 849 2004.0 No RF 的关键词 tsc/rheb/mtor/s6k cassette inappropriate activation induces irs1/2 depletion-insulin resistance-cell survival deficiencies; enhancing insulin sensitivity; insulin resistance; tsc1-2 tumor suppressor controls insulin-p13k signaling 论文题目 被引 年份 刊名 第一作者 第一机构、国家 absence of s6k1 protects against age- and diet-induced obesity while enhancing insulin sensitivity 362 2004 NATURE UM SH Friedrich Miescher Inst Biomed Res, Switzerland the tsc1-2 tumor suppressor controls insulin-p13k signaling via regulation of irs proteins 278 2004 J CELL BIOL HARRINGTON LS Inst Canc Res, England inappropriate activation of the tsc/rheb/mtor/s6k cassette induces irs1/2 depletion, insulin resistance, and cell survival deficiencies 209 2004 CURR BIOL SHAH OJ Salk Inst Biol Studies, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 14863 3 315 405 2005.6 No RF 的关键词 ras/erk signaling; site-specific ribosomal protein s6 phosphorylation; mitogen-activated protein kinase-dependent s6 kinase pathway; protein synthesis; rapamycin-sensitive 5 ''-terminal oligopyrimidine mrna translation 论文题目 被引 年份 刊名 第一作者 第一机构、国家 s6k1(-/-)/s6k2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5 '-terminal oligopyrimidine mrna translation and reveal a mitogen-activated protein kinase-dependent s6 kinase pathway 226 2004 MOL CELL BIOL PENDE M INSERM 584, France ribosomal protein s6 phosphorylation: from protein synthesis to cell size 118 2006 TRENDS BIOCHEM SCI RUVINSKY I Hebrew Univ Jerusalem, Israel ras/erk signaling promotes site-specific ribosomal protein s6 phosphorylation via rsk and stimulates cap-dependent translation 61 2007 J BIOL CHEM ROUX PP Univ Montreal, Canada RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 9782 3 395 574 2006.0 Yes RF 的关键词 mtor inhibition induces upstream receptor tyrosine kinase signaling; rapamycin induces feedback activation; akt signaling; rapamycin inhibition; activates akt 论文题目 被引 年份 刊名 第一作者 第一机构、国家 mtor inhibition induces upstream receptor tyrosine kinase signaling and activates akt 318 2006 CANCER RES O'REILLY KE Mem Sloan Kettering Canc Ctr, USA activation of akt and eif4e survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition 162 2005 CANCER RES SUN SY Emory Univ, USA rapamycin induces feedback activation of akt signaling through an igf-1r-dependent mechanism 94 2007 ONCOGENE WAN X NCI, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 7986 2 72 120 2008.0 Yes RF 的关键词 erk mapk signaling; hormone-refractory prostate cancer; mapk pathway activation; human cancer; pi3k-dependent feedback loop; preclinical mouse model 论文题目 被引 年份 刊名 第一作者 第一机构、国家 inhibition of mtorc1 leads to mapk pathway activation through a pi3k-dependent feedback loop in human cancer 77 2008 J CLIN INVEST CARRACEDO A 77 Ave Louis Pasteur, USA targeting akt/mtor and erk mapk signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model 43 2008 J CLIN INVEST KINKADE CW Columbia Univ, USA RF ID 核心论文数 被引用篇数 总被引次数 平均出版年 是否为热点 12550 2 70 108 2008.0 Yes RF 的关键词 oncogenic cellular transformation; class ipi3k; pi3k/akt pathway; cancer; drug discovery 论文题目 被引 年份 刊名 第一作者 第一机构、国家 drug discovery approaches targeting the pi3k/akt pathway in cancer 65 2008 ONCOGENE GARCIA-ECHEVERRIA C Novartis Inst Biomed Res, Switzerland class ipi3k in oncogenic cellular transformation 43 2008 ONCOGENE ZHAO L Scripps Res Inst, USA
详情见 PAPP2C Interacts with the Atypical Disease Resistance Protein RPW8.2 and Negatively Regulates Salicylic Acid-Dependent Defense Responses in Arabidopsis 下图是YFP-PAPP2C（绿色）在细胞中的分布，叶绿体（红色）分布在细胞边缘
MAPK/ERK pathway From Wikipedia, the free encyclopedia Jump to: navigation , search Key components of the MAPK/ERK pathway. "P" represents phosphate , which communicates the signal. Top, epidermal growth factor (EGF) binds to the EGF receptor (EGFR) in the cell membrane, starting the cascade of signals. Further downstream, phosphate signal activates MAPK (also known as ERK). Bottom, signal enters the cell nucleus and causes transcription of DNA, which is then expressed as protein. The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, including MAPK (originally called ERK), which communicate by adding phosphate groups to a neighboring protein, which acts as an "on" or "off" switch. When one of the proteins in the pathway is mutated, it can be stuck in the "on" or "off" position, which is a necessary step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Drugs that reverse the "on" or "off" switch are being investigated as cancer treatments. Contents 1 Coupling cell surface receptors to G proteins 2 Kinase cascade 3 Regulation of translation and transcription 4 Clinical significance 5 See also 6 References 7 External links // Coupling cell surface receptors to G proteins Receptor-linked tyrosine kinases such as the epidermal growth factor receptor (EGFR) are activated by extracellular ligands . Binding of epidermal growth factor (EGF) to the EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. The EGFR becomes phosphorylated on tyrosine residues. Docking proteins such as GRB2 contains an SH2 domain that binds to the phosphotyrosine residues of the activated receptor . GRB2 binds to the guanine nucleotide exchange factor SOS by way of the two SH3 domains of GRB2. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated . Activated SOS then promotes the removal of GDP from a member of the Ras subfamily (most notably H-Ras or K-Ras ). Ras can then bind GTP and become active. Apart from EGFR, other cell surface receptors that can activate this pathway via GRB2 include Trk A/B , Fibroblast growth factor receptor (FGFR) and PDGFR . Kinase cascade Activated Ras activates the protein kinase activity of RAF kinase . RAF kinase phosphorylates and activates MEK . MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK). RAF, MEK, and MAPK are all serine/threonine-selective protein kinases . In the technical sense, RAF, MEK, and MAPK are all mitogen -activated kinases, as is MNK (see below). MAPK was originally called " extracellular signal-regulated kinases " ( ERKs ) and "microtubule-associated protein kinase" (MAPK). One of the first proteins known to be phosphorylated by ERK was a microtubule-associated protein (MAP). As discussed below, many additional targets for phosphorylation by MAPK were later found, and the protein was re-named "mitogen-activated protein kinase" (MAPK). The series of kinases from RAF to MEK to MAPK is an example of a protein kinase cascade. Such series of kinases provide opportunities for feedback regulation and signal amplification. Regulation of translation and transcription Three of the many proteins that are phosphorylated by MAPK are shown in the Figure. One effect of MAPK activation is to alter the translation of mRNA to proteins. MAPK phosphorylates 40S ribosomal protein S6 kinase ( RSK ). This activates RSK, which, in turn, phosphorylates ribosomal protein S6 . Mitogen-activated protein kinases that phosphorylate ribosomal protein S6 were the first to be isolated . MAPK regulates the activities of several transcription factors . MAPK can phosphorylate C-myc . MAPK phosphorylates and activates MNK, which, in turn, phosphorylates CREB . MAPK also regulates the transcription of the C-Fos gene. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle . The 22q11, 1q42, and 19p13 genes are associated with schizophrenia , schizoaffective , bipolar , and migraines by affecting the ERK pathway. In simpler terms, the mitogen binds to the membrane ligand. This means that Ras (a GTPase) can swap its GDP for a GTP. It can now activate MAP3K (e.g., Raf), which activates MAP2K, which activates MAPK. MAPK can now activate a transcription factor, such as myc. Clinical significance This section requires expansion . Uncontrolled growth is a necessary step for the development of all cancers. In many cancers (eg melanoma ), a defect in the MAP/ERK pathway leads to that uncontrolled growth. Many compounds can inhibit steps in the MAP/ERK pathway, and therefore are potential drugs for treating cancer. eg. Hodgkin disease The first drug licensed to act on this pathway is sorafenib - a Raf kinase inhibitor. Other Raf inhibitors: SB590885 , PLX4720 , XL281 , RAF265 , PLX4032 . Some MEK inhibitors: XL518 , CI-1040 , PD035901 , AZD6244 , GSK1120212 Protein microarray analysis can be used to detect subtle changes in protein activity in signaling pathways. See also Janus kinase Phosphatase Adaptor protein G protein-coupled receptor References ^ Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W (Dec 2005). "Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway" . The Biochemical journal 392 (Pt 2): 249–61. doi : 10.1042/BJ20050908 . PMID 16293107 . ^ Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family" . Molecular systems biology 1 : 2005.0008. doi : 10.1038/msb4100012 . PMID 16729043 . ^ Zarich N, Oliva JL, Martínez N, et al. (Aug 2006). "Grb2 is a negative modulator of the intrinsic Ras-GEF activity of hSos1" . Molecular Biology of the Cell 17 (8): 3591–7. doi : 10.1091/mbc.E05-12-1104 . PMID 16760435 . ^ a b Avruch J, Khokhlatchev A, Kyriakis JM, et al. (2001). "Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade" . Recent Progress in Hormone Research 56 : 127–55. doi : 10.1210/rp.56.1.127 . PMID 11237210 . http://rphr.endojournals.org/cgi/pmidlookup?view=longpmid=11237210 . ^ Pende M, Um SH, Mieulet V, et al. (Apr 2004). "S6K1,(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway" . Molecular and cellular biology 24 (8): 3112–24. doi : 10.1128/MCB.24.8.3112-3124.2004 . PMID 15060135 . PMC 381608 . http://mcb.asm.org/cgi/pmidlookup?view=longpmid=15060135 . ^ http://content.karger.com/ProdukteDB/produkte.asp?Doi=68621 "The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer" 2002 ^ http://www.tripdatabase.com/spider.html?itemid=717131 "Advances in the Development of Cancer Therapeutics Directed against the RAS-Mitogen-Activated Protein Kinase Pathway" 2008 ^ http://www.ncbi.nlm.nih.gov/pubmed/9989833 ? "Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors." 1999 ^ http://www.ncbi.nlm.nih.gov/pubmed/17126425 ? "Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance." 2007 ^ a b c Kwong-Kwok Wong (2009). . http://www.bentham.org/pra/samples/pra4-1/0004PRA.pdf . ^ http://bloodjournal.hematologylibrary.org/cgi/content/abstract/102/3/1019 "MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival" Blood. 2003 ^ http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01037127 ^ Calvert, Valerie S. et al; Tang, Yihui; Boveia, Vince; Wulfkuhle, Julie; Schutz-Geschwender, Amy; Olive, D. Michael; Liotta, Lance A.; Petricoin, Emanuel F. (2004). "Development of Multiplexed Protein Profiling and Detection Using Near Infrared Detection of Reverse-Phase Protein Microarrays" . Clinical Proteomics Journal 1 : 81–89. doi : 10.1385/CP:1:1:081 . http://biosupport.licor.com./docs/2005/Petricoin_Clinical_Proteomics_paper.pdf .
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