Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met.
Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met.
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DOI：
10.1038/jid.2010.13
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发表时间：
2010-06
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黑色素瘤是由复杂的遗传和表观遗传变化引起的，导致不受控制的增殖、侵袭和转移性疾病。信号蛋白通过与其受体丛蛋白和神经磷脂的相互作用，是轴突引导的关键调节因子。丛蛋白受体的异常表达与多种肿瘤的进展有关。丛状蛋白B1，信号蛋白4D受体，激活致癌受体c-Met和ErbB-2，导致推测它通过刺激这些受体促进肿瘤生长。我们发现丛蛋白B1在体内转移性黑色素瘤和深度侵袭性原发肿瘤中缺失。将Plexin B1导入人转移性黑色素瘤细胞系可抑制增殖，增强迁移，刺激Akt活化，并使细胞抵抗顺铂诱导的凋亡。出乎意料的是，Plexin B1在c-Met配体（肝细胞生长因子）的作用下抑制了高达54%的c-Met，同时c-Met底物Gab1的磷酸化也随之丧失。在进展依赖c-Met的黑色素瘤中，丛蛋白B1的缺失被预测为一种典型的肿瘤抑制蛋白。然而，由于Plexin B1激活Akt并抑制细胞凋亡，Plexin B1可能在黑色素瘤的进展中发挥复杂的作用，并可能是肿瘤对化疗药物敏感性的预测指标。
Melanoma arises through complex genetic and epigenetic changes resulting in uncontrolled proliferation, invasion and metastatic disease. Semaphorins are critical regulators of axon guidance through interaction with their receptors, Plexins and neuropilins. Aberrant expression of Plexin receptors is been linked with progression of a variety of tumors. Plexin B1, the Semaphorin 4D receptor, activates the oncogenic receptors c-Met and ErbB-2, leading to speculation that it promotes tumor growth through stimulation of these receptors. We show that Plexin B1 is lost in metastatic melanoma and in deeply invasive primary tumors in vivo. Introduction of Plexin B1 into a human metastatic melanoma cell line suppressed proliferation, enhanced migration, stimulated Akt activation, and rendered cells resistant to cis-platin induced apoptosis. Unexpectedly, Plexin B1 inhibited c-Met by up to 54% in response to the c-Met ligand, hepatocyte growth factor, with a concordant loss of phosphorylation of the c-Met substrate, Gab1. Loss of Plexin B1 is predicted to function as a classic tumor suppressor protein in melanomas in which progression is c-Met dependent. However, because Plexin B1 activates Akt, and suppresses apoptosis, Plexin B1 likely plays a complex role in melanoma progression, and may be a predictive marker for tumor sensitivity to chemotherapeutic agents.
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