Chen Xu, Wu Qiuxia, Depeille Philippe, Chen Peirong, Thornton Sophie, Kalirai Helen, Coupland Sarah E, Roose Jeroen P, Bastian Boris C
Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Cancer Cell. 2017 May 8;31(5):685-696.e6. doi: 10.1016/j.ccell.2017.04.002.
Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.
GNAQ或GNA11突变导致的Gαq信号通路组成性激活在超过80%的葡萄膜黑色素瘤（UM）中发生，并激活丝裂原活化蛋白激酶（MAPK）。蛋白激酶C（PKC）被认为是一个关联因素，但具体机制细节仍不清楚。我们确定PKCδ和ɛ是激活GNAQ突变黑色素瘤中MAPK所必需且足够的。MAPK激活依赖于Ras，并且由RasGRP3引起，RasGRP3在UM中因GNAQ/11突变而显著且选择性地过表达。RasGRP3激活通过PKCδ和ɛ依赖性磷酸化以及不依赖PKC的二酰基甘油（DAG）介导的膜募集发生，这可能解释了PKC抑制剂对持久抑制UM中MAPK的作用有限。这些发现将RasGRP3确定为致癌性GNAQ/11驱动的癌症的治疗靶点。
