Rit subfamily small GTPases: regulators in neuronal differentiation and survival

Abstract

Ras family small GTPases serve as binary molecular switches to regulate a broad array of cellular signaling cascades, playing essential roles in a vast range of normal physiological processes, with dysregulation of numerous Ras-superfamily G-protein-dependent regulatory cascades underlying the development of human disease. However, the physiological function for many "orphan" Ras-related GTPases remain poorly characterized, including members of the Rit subfamily GTPases. Rit is the founding member of a novel branch of the Ras subfamily, sharing close homology with the neuronally expressed Rin and Drosophila Ric GTPases. Here, we highlight recent studies using transgenic and knockout animal models which have begun to elucidate the physiological roles for the Rit subfamily, including emerging roles in the regulation of neuronal morphology and cellular survival signaling, and discuss new genetic data implicating Rit and Rin signaling in disorders such as cancer, Parkinson's disease, autism, and schizophrenia.

Keywords: CA; CCI; CREB; CRIB; CaM; Cdc42/Rac interactive binding; DA; DAT; DN; EGF; ERK; Epac; G protein coupled receptor; GAP; GEF; GPCR; GTPase; GTPase activating protein; HSP27; IFNγ; JNK; MAPK; MAPK kinase (also MAP2K); MAPK-activated protein kinase 2 (MAPKAPK2); MEFs; MK2; MKK; MSK1/2; NGF; Neuron; PACAP38; PD; PI3K; PKA; PKC; PMA; Parkinson's disease; RGL3; ROS; RTK; RalGDS-like 3; Ras GTPase; Ras-related protein which interacted with calmodulin; Ric; Ric (Ras)-related gene expressed in neural tissues; Ric (Ras)-related gene expressed throughout the organism; Rin; Rit; SOS; Signaling; TBI; TNFα; TrkA; c-Jun N-terminal protein kinase; cAMP; cAMP response element binding protein; calmodulin; constitutively active; controlled cortical impact; cyclic adenosine monophosphate; dominant negative; dopamine; dopamine transporter; epidermal growth factor; exchange protein directly activated by cAMP; extracellular-signal regulated protein kinase; guanine nucleotide exchange factor; guanosine triphosphatase; heat shock protein 27; interferon-γ; mitogen- and stress-activated protein kinase 1/2; mitogen-activated protein kinase; mouse embryonic fibroblasts; nerve growth factor; phorbol 12-myristate 13-acetate; phosphatidylinositol 3-kinase; pituitary adenylate cyclase activated polypeptide 38; protein kinase A; protein kinase C; reactive oxygen species; receptor tyrosine kinase; son of sevenless; traumatic brain injury; tropomyosin receptor kinase A; tumor necrosis factor α.