Non-canonical signal pathway for Crk in breast cancer

乳腺癌中 Crk 的非经典信号通路

• 批准号: 8701004
• 负责人: RAYMOND B BIRGE
• 金额: $ 27.88万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-12 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701004
• 关键词: Adaptor Signaling Protein; Address; Adenocarcinoma; Affinity; Apoptotic; Behavior; Binding; Binding Sites; Biological Assay; Biological Process; Breast; Breast Cancer Cell; Cancer Patient; Cancer Prognosis; Cancer cell line; Cell physiology; Cell-Cell Adhesion; Cells; Chickens; Clinical Research; Data; Detection; Development; Embryo; Epidermal Growth Factor Receptor; Eukaryotic Cell; Fatty acid glycerol esters; Fibroblasts; Generations; Glioblastoma; Guanine Nucleotide Exchange Factors; Human; Immigration; Intervention; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; N-terminal; Names; Neoplasm Metastasis; Ovarian; PTB Domain; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Positive Lymph Node; Predisposition; Prognostic Marker; Property; Protein Binding; Protein Tyrosine Kinase; Protein-Kinase Oncogenes; Proteins; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regulation; Research; Role; SH3 Domains; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Small Interfering RNA; Stomach; Stomach Carcinoma; Structure; Testing; Therapeutic; Translating; Tyrosine; Tyrosine Phosphorylation; Tyrosine Phosphorylation Site; Tyrosine-Kinase Oncogenes; base; cancer cell; cell behavior; cell growth; cell motility; cell transformation; cis trans isomerization; clinically significant; in vivo; innovation; malignant breast neoplasm; malignant phenotype; member; mouse model; novel; overexpression; polyclonal antibody; protein complex; protein expression; protein function; protein protein interaction; proto-oncogene protein c-crk; receptor; sarcoma; screening; synovial sarcoma; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): The Src Homology 2 (SH2) and Src Homology 3 (SH3) domain-containing protein Crk is the prototypical member of a class of adaptor proteins that play essential roles in signaling downstream of tyrosine kinases. By promoting the assembly of protein complexes mediated by the SH2 and SH3 domains, evidence accumulated over the past two decades has elucidated a canonical pathway for Crk signaling whereby the SH2 domain binds tyrosine phosphorylated proteins and the N-terminal SH3 domain (SH3N) binds guanine-nucleotide exchange factors that activate Rac1, Rap1, and Ras. The clinical significance of Crk in human cancer has been enumerated in recent years, as Crk is frequently over-expressed in several different cancers, including breast, ovarian, gastric, lung, glioblastoma, and sarcomas and siRNA-mediated knockdown of Crk reverses the malignant and metastatic features of these cancers. These observations have led to a new urgency to understand the mechanisms by which Crk promotes malignant transformation in the hope that new information can be exploited to develop therapeutics, particularly for tumors with a predisposition towards invasion and metastasis. In this application we have identified a new signaling paradigm for Crk by the identification of two previously uncharacterized tyrosine phosphorylation sites located within the carboxyl-terminal SH3 (SH3C) domain, an atypical SH3 domain that has no clear biological function. Tyr251 is located in the highly conserved RT-loop of the Crk SH3C while Tyr239 is located at the boundary of the linker and SH3C and comprises a region of Crk implicated in the negative regulation and auto-clamping of the SH3C to the SH3N. The central hypothesis of this application is that Crk, in addition to its canonical role as an adaptor protein, has an unconventional role in signal transduction through phosphorylation of Tyr251 and Tyr239, that define new binding sites allowing recruitment of SH2 and/or PTB domain containing proteins. The recruitment of these proteins may initiate post-phosphorylation-dependent signaling pathways relevant to cell transformation. Both sites are tyrosine phosphorylated by EGFR and ErbB2 receptors suggesting this research is directly relevant to signaling in cancer cells that have overexpressed or activated receptor tyrosine kinases oncogenes. In recent years, an emerging body of evidence suggests that Crk proteins are overexpressed in human tumors and the expression levels correlate with aggressive and malignant behavior of cancer cells. These properties of Crk proteins make them potential cancer prognosis markers and therapeutic targets.

描述（由申请人提供）：SRC同源性2（SH2）和SRC同源性3（SH3）含结构域的蛋白CRK是一类衔接蛋白的典型成员，它们在酪氨酸激酶下游信号下的信号传导中起着重要作用。通过促进由SH2和SH3结构域介导的蛋白质复合物的组装，在过去的二十年中积累的证据阐明了CRK信号传导的规范途径，SH2域结合酪氨酸磷酸化的蛋白质和N-末端SH3结构域（SH3N）结合了岛氨酸 - nucleeletiide Chrence1 anc1 and Accap rac1 rac1 rac1，近年来，CRK在人类癌症中的临床意义已被列举，因为CRK在几种不同的癌症中经常表达过表达，包括乳腺癌，卵巢，胃，肺癌，肺细胞瘤，肉瘤，以及siRNA介导的CRK敲低CRK的CRK逆转逆转这些癌症的恶性和转移性特征。这些观察结果导致了新的紧迫性，以了解CRK促进恶性转化的机制，希望可以利用新信息来开发治疗疗法，特别是对于对侵袭和转移倾向的肿瘤。 在此应用中，我们通过鉴定位于羧基末端SH3（SH3C）结构域内的两个先前未表征的酪氨酸磷酸化位点来鉴定CRK的新信号范式，这是一个没有明确的生物学功能的非典型SH3结构域。 Tyr251位于CRK SH3C的高度保守的RT环中，而Tyr239位于接头和SH3C的边界上，并包括与SH3C负面调节和自动缩短到SH3N的CRK区域。该应用的中心假设是，除了其作为适配器蛋白的规范作用外，CRK在信号转导中具有非常规的作用，它通过Tyr251和Tyr239的磷酸化来定义新的结合位点，从而允许募集SH2和/或PTB结构域含有蛋白质。这些蛋白质的募集可能引发与细胞转化有关的磷酸化后信号传导途径。这两个位点都是由EGFR和ERBB2受体磷酸化的酪氨酸，表明这项研究与过表达或活化的受体酪氨酸激酶癌基因酶的癌细胞中的信号直接相关。近年来，新出现的证据表明，CRK蛋白在人肿瘤中过表达，表达水平与癌细胞的侵略性和恶性行为相关。 CRK蛋白的这些特性使它们成为潜在的癌症预后标志物和治疗靶标。