Neudauer C L, Joberty G, Tatsis N, Macara I G
Center for Cell Signaling University of Virginia Charlottesville, Virginia, 22908, USA.
Curr Biol. 1998 Oct 22;8(21):1151-60. doi: 10.1016/s0960-9822(07)00486-1.
Rho-family GTPases have central roles in cytoskeletal organization, proliferation, differentiation and apoptosis. Multiple factors possessing overlapping specificities for Rho GTPases have been identified. The Rho GTPases Cdc42 and Rac share many regulators and effectors, yet produce different phenotypes when expressed as gain-of-function mutants in cells. The Rho-family member TC10 has remained almost completely uncharacterized, so it was of interest to determine whether TC10 has unique cellular effects and interacts with the same targets as Cdc42 and Rac.
A gain-of-function TC10 mutant protein expressed in fibroblasts induced cell rounding, loss of stress fibers and formation of peripheral extensions. The extensions were longer than those induced by the analogous Cdc42 mutant protein. Cells expressing TC10 also possessed fewer membrane ruffles and stress fibers than those expressing Cdc42. TC10 mRNA was most highly expressed in heart and skeletal muscle. The GTPase activity of TC10 was lower than that of Cdc42, and TC10 possessed a lower affinity for, but greater responsiveness to, the p50Rho GTPase-activating protein (p50RhoGAP) than did Cdc42. TC10 stimulated Jun N-terminal kinase (JNK) and p21-activated kinase (PAK) activities and interacted with a set of effectors (alpha-, beta- and gammaPAK, MRCKalpha/beta, MLK2, N-WASP and MSE55) that overlaps with those for Cdc42 and Rac. TC10 did not interact with MLK3 or WASP, and interacted only weakly with ACK-1.
TC10 possesses distinct features, but exhibits a phenotype most closely related to that of Cdc42. It interacts with a similar subset of effectors to Cdc42 but not with MLK3, WASP or ACK-1. It is regulated differentially by p50RhoGAP.
Rho家族GTP酶在细胞骨架组织、增殖、分化和凋亡中起核心作用。已鉴定出多种对Rho GTP酶具有重叠特异性的因子。Rho GTP酶Cdc42和Rac共享许多调节因子和效应器，但在细胞中作为功能获得性突变体表达时会产生不同的表型。Rho家族成员TC10几乎完全未被表征，因此确定TC10是否具有独特的细胞效应以及是否与Cdc42和Rac的相同靶点相互作用很有意义。
在成纤维细胞中表达的功能获得性TC10突变蛋白诱导细胞变圆、应力纤维丧失和外周延伸的形成。这些延伸比类似的Cdc42突变蛋白诱导的延伸更长。表达TC10的细胞也比表达Cdc42的细胞具有更少的膜皱褶和应力纤维。TC10 mRNA在心脏和骨骼肌中表达最高。TC10的GTP酶活性低于Cdc42，并且与p50Rho GTP酶激活蛋白（p50RhoGAP）相比，TC10对其亲和力较低，但反应性更高。TC10刺激Jun N末端激酶（JNK）和p21激活激酶（PAK）活性，并与一组效应器（α-、β-和γPAK、MRCKα/β、MLK2、N-WASP和MSE55）相互作用，这些效应器与Cdc42和Rac的效应器重叠。TC10不与MLK3或WASP相互作用，仅与ACK-1弱相互作用。
TC10具有独特的特征，但表现出与Cdc42最密切相关的表型。它与Cdc42的效应器子集相似，但不与MLK3、WASP或ACK-1相互作用。它受p50RhoGAP的不同调节。
