Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, U.S.A.
Biochem J. 2020 Aug 14;477(15):2755-2770. doi: 10.1042/BCJ20200442.
RIT1 is a member of the Ras family of GTPases that direct broad cellular physiological responses through tightly controlled signaling networks. The canonical Ras GTPases are well-defined regulators of the RAF/MEK/ERK pathway and mutations in these are pathogenic in cancer and a class of developmental disorders termed RASopathies. Emerging clinical evidences have now demonstrated a role for RIT1 in RASopathies, namely Noonan syndrome, and various cancers including lung adenocarcinoma and myeloid malignancies. While RIT1 has been mostly described in the context of neuronal differentiation and survival, the mechanisms underlying aberrant RIT1-mediated signaling remain elusive. Here, we will review efforts undertaken to characterize the biochemical and functional properties of the RIT1 GTPase at the molecular, cellular, and organismal level, as well as provide a phenotypic overview of different human conditions caused by RIT1 mutations. Deeper understanding of RIT1 biological function and insight to its pathogenic mechanisms are imperative to developing effective therapeutic interventions for patients with RIT1-mutant Noonan syndrome and cancer.
RIT1 是 Ras 家族 GTP 酶的成员，通过紧密控制的信号网络指导广泛的细胞生理反应。典型的 Ras GTP 酶是 RAF/MEK/ERK 途径的明确调节剂，这些基因的突变在癌症和一类称为 RAS 病的发育障碍中是致病的。新出现的临床证据表明，RIT1 在 RAS 病中起作用，即 Noonan 综合征和各种癌症，包括肺腺癌和髓系恶性肿瘤。虽然 RIT1 主要在神经元分化和存活的背景下被描述，但异常的 RIT1 介导的信号的机制仍然难以捉摸。在这里，我们将回顾为表征 RIT1 GTP 酶在分子、细胞和机体水平上的生化和功能特性所做的努力，并提供由 RIT1 突变引起的不同人类疾病的表型概述。深入了解 RIT1 的生物学功能及其致病机制对于为 RIT1 突变型 Noonan 综合征和癌症患者开发有效的治疗干预措施至关重要。
