Cross Talk between Receptor Guanylyl Cyclase C and c-src Tyrosine Kinase Regulates Colon Cancer Cell Cytostasis
Cross Talk between Receptor Guanylyl Cyclase C and c-src Tyrosine Kinase Regulates Colon Cancer Cell Cytostasis
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DOI：
10.1128/mcb.00001-09
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发表时间：
2009-10-01
影响因子：
5.3
通讯作者：
Visweswariah, Sandhya S.
中科院分区：
文献类型：
--
作者：
Basu, Nirmalya;Bhandari, Rashna;Visweswariah, Sandhya S.
C-src在结直肠癌中的激活增加是临床预后不良的一个指标，提示对c-src下游效应因子的识别可能会导致新的治疗途径。鸟苷酸环化酶C(GC-C)是胃肠激素鸟苷和尿鸟苷的受体，也是细菌耐热肠毒素的受体。尽管GC-C被其配体激活后升高细胞内环鸟苷酸(CGMP)水平并抑制细胞增殖，但其在结直肠癌和隐匿性转移中的持续表达使其成为恶性肿瘤的标志。我们在这里表明，GC-C是c-src抑制磷酸化的底物，导致配体介导的cGMP产生减少。因此，结肠细胞中活跃的c-src可以克服GC-C介导的细胞周期调控。此外，c-src SH2结构域与磷酸化的GC-C的对接导致c-src的共定位和进一步激活。因此，我们提出了一种新的c-src激活的前馈机制，该机制是由受体GC和酪氨酸激酶之间的串扰诱导的。我们的发现对于理解结直肠癌进展和治疗的分子机制具有重要意义。
Increased activation of c-src seen in colorectal cancer is an indicator of a poor clinical prognosis, suggesting that identification of downstream effectors of c-src may lead to new avenues of therapy. Guanylyl cyclase C (GC-C) is a receptor for the gastrointestinal hormones guanylin and uroguanylin and the bacterial heat-stable enterotoxin. Though activation of GC-C by its ligands elevates intracellular cyclic GMP (cGMP) levels and inhibits cell proliferation, its persistent expression in colorectal carcinomas and occult metastases makes it a marker for malignancy. We show here that GC-C is a substrate for inhibitory phosphorylation by c-src, resulting in reduced ligand-mediated cGMP production. Consequently, active c-src in colonic cells can overcome GC-C-mediated control of the cell cycle. Furthermore, docking of the c-src SH2 domain to phosphorylated GC-C results in colocalization and further activation of c-src. We therefore propose a novel feed-forward mechanism of activation of c-src that is induced by cross talk between a receptor GC and a tyrosine kinase. Our findings have important implications in understanding the molecular mechanisms involved in the progression and treatment of colorectal cancer.