p140Sra-1 (Specifically Rac1-associated Protein) Is a Novel Specific Target for Rac1 Small GTPase

Abstract

Rac1 small GTPase plays pivotal roles in various cell functions such as cell morphology, cell polarity, and cell proliferation. We have previously identified IQGAP1 from bovine brain cytosol as a target for Rac1 by an affinity purification method. By using the same method, we purified a specifically Rac1-associated protein with a molecular mass of about 140 kDa (p140) from bovine brain cytosol. This protein interacted with guanosine 5-(3-O-thio)triphosphate (GTP␥S)⅐glutathione S-transferase (GST)-Rac1 but not with the GDP⅐GST-Rac1, GTP␥S⅐GST-Cdc42, or GTP␥S⅐GST-RhoA. The amino acid sequences of this protein revealed that p140 is identified as a product of KIAA0068 gene. We denoted this protein as Sra-1 (Specifically Rac1-associated protein). Recombinant Sra-1 interacted with GTP␥S⅐GST-Rac1 and weakly with GDP⅐Rac1 but not with GST-Cdc42 or GST-RhoA. The N-terminal domain of Sra-1 (1-407 amino acids) was responsible for the interaction with Rac1. Myc-tagged Sra-1 and the deletion mutant capable of interacting with Rac1, but not the mutants unable to bind Rac1, were colocalized with dominant active Rac1Val-12 and cortical actin filament at the Rac1 Val-12 -induced membrane ruffling area in KB cells. Sra-1 was cosedimented with filamentous actin (F-actin), indicating that Sra-1 directly interacts with F-actin. These results suggest that Sra-1 is a novel and specific target for Rac1.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…protein 48 , interacts with fragile X mental retardation protein (FMRP) [49][50][51][52][53] , which regulates the dendritic targeting of mRNAs 54 and controls mRNA decay and protein synthesis in the neuronal soma and at spines 50 . FMRP tethers specific mRNAs to CYFIP1, which then sequesters the capbinding protein eIF4E and mediates translational repression 55 ( Figure 1).…”

“…The equilibrium of the two complexes is controlled by small GTPase Rac1, which alters the conformation of CYFIP1 47,48,53 . The heteropentameric WRC, consisting of the proteins WAVE1/2/3, ABI1/2, NCKAP1, HPSC300 and CYFIP1 or CYFIP2, is one of the critical modulators of actin filament reorganization in neurons 56 .…”

Rho-linked genes and neurological disorders

“…In mammals, CYFIP1 (also known as p140/Sra-1) was initially identified as a target of Rac1 [48], whereas CYFIP2 (also called PIR121) was found to be part of the inactive WAVE protein complex [20], that is responsive to Rac signaling. In its inactive state, this complex includes WAVE1, which is localized to spines in hippocampal neurons, along with four other proteins: HSPC 300, Nap125, Abi2 and PIR121.…”

Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy

“…Moreover, Wave-1, a member of a scaffolding complex important for relaying signals from the GTPases to the actin cytoskeleton, has been associated with both sensorimotor development and learning and memory in mice (Soderling et al 2003). Also of relevance is that the cytoplasmic FMR1-interacting protein (CYFIP1) (Schenck et al 2001) was originally characterised by its ability to bind the active small GTPase Rac1 (Kobayashi et al 1998). Another example is the cyclin-dependent kinase 5, which is essential for normal brain development in mice (Ohshima et al 1996).…”