Hoefen Ryan J, Berk Bradford C
Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
J Cell Sci. 2006 Apr 15;119(Pt 8):1469-75. doi: 10.1242/jcs.02925.
The G-protein-coupled receptor (GPCR)-kinase-interacting proteins 1 and 2 (GIT1 and GIT2) are ubiquitous multidomain proteins involved in diverse cellular processes. They traffic between three distinct cellular compartments (cytoplasmic complexes, focal adhesions and the cell periphery) through interactions with proteins including ARF, Rac1 and Cdc42 GTPases, p21-activated kinase (PAK), PAK-interacting exchange factor (PIX), the kinase MEK1, phospholipase Cgamma (PLCgamma) and paxillin. GITs and PIX cooperate to form large oligomeric complexes to which other proteins are transiently recruited. Activation of Rac1 and Cdc42 drives association of PAK with these oligomers, which unmasks the paxillin-binding site in GITs that recruits them to focal complexes. There, they regulate cytoskeletal dynamics by feedback inhibition of Rac1. GITs also participate in receptor internalization by regulating membrane trafficking between the plasma membrane and endosomes, targeting ARF GTPases through their ARF GTPase-activating protein (ARF-GAP) activity. Furthermore, GITs act as scaffolds to control spatial activation of several signaling molecules. Finally, recent results suggest pathogenic roles for GIT proteins in Huntington's disease and HIV infection.
G蛋白偶联受体（GPCR）激酶相互作用蛋白1和2（GIT1和GIT2）是普遍存在的多结构域蛋白，参与多种细胞过程。它们通过与包括ARF、Rac1和Cdc42 GTP酶、p21激活激酶（PAK）、PAK相互作用交换因子（PIX）、激酶MEK1、磷脂酶Cγ（PLCγ）和桩蛋白等蛋白质相互作用，在三个不同的细胞区室（细胞质复合物、粘着斑和细胞周边）之间穿梭。GIT蛋白和PIX协同形成大型寡聚复合物，其他蛋白质会暂时募集到该复合物上。Rac1和Cdc42的激活促使PAK与这些寡聚体结合，从而暴露GIT蛋白中可将它们募集到粘着斑复合物的桩蛋白结合位点。在那里，它们通过对Rac1的反馈抑制来调节细胞骨架动力学。GIT蛋白还通过调节质膜和内体之间的膜运输，利用其ARF GTP酶激活蛋白（ARF-GAP）活性靶向ARF GTP酶，从而参与受体的内化过程。此外，GIT蛋白作为支架来控制几种信号分子的空间激活。最后，最近的研究结果表明GIT蛋白在亨廷顿舞蹈病和HIV感染中具有致病作用。
