Regulation of dendritic arborization by BCR Rac1 GTPase-activating protein, a new substrate of protein tyrosine phosphatase receptor T

Abstract

SummaryDendritic arborization is important for neuronal development as well as the formation of neural circuits. Rac1 is a member of the Rho GTPase family that serve as regulators of neuronal development. Breakpoint cluster region protein (BCR) is a Rac1 GTPase-activating protein that is abundantly expressed in the central nervous system. Here, we show that BCR plays a key role in neuronal development. Dendritic arborization and actin polymerization were attenuated by overexpression of BCR in hippocampal neurons. Knockdown of BCR using specific shRNAs increased the dendritic arborization as well as actin polymerization. The number of dendrites in null mutant BCR 2/2 mice was considerably increased compared with that in wild-type mice. We found that the function of the BCR GTPaseactivating domain could be modulated by protein tyrosine phosphatase receptor T (PTPRT), which is expressed principally in the brain. We demonstrate that tyrosine 177 of BCR was the main target of PTPRT and the BCR mutant mimicking dephosphorylation of tyrosine 177 alleviated the attenuation of dendritic arborization. Additionally the attenuated dendritic arborization found upon BCR overexpression was relieved upon co-expression of PTPRT. When PTPRT was knocked down by a specific shRNA, the dendritic arborization was significantly reduced. The activity of the BCR GTPase-activating domain was modulated by means of conversions between the intra-and inter-molecular interactions, which are finely regulated through the dephosphorylation of a specific tyrosine residue by PTPRT. We thus show conclusively that BCR is a novel substrate of PTPRT and that BCR is involved in the regulation of neuronal development via control of the BCR GTPase-activating domain function by PTPRT.

Proteomic Analysis of the SH2Domain-containing Leukocyte Protein of 76 kDa (SLP76) Interactome

“…The GTPase activity of Bcr is positively regulated by a Protein Tyrosine Phosphatase Receptor in neurons. Bcr is indeed highly expressed in the central nervous system where it decreases dendrite formation by negatively regulating actin polymerization in neurons (50).…”

Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex

“…These alterations in Tiam1 and Bcr function correlate with a transient increase in Rac1 activity (Figures 6I and 6J), suggesting that EphBs control Rac1 activation by coordinately regulating the opposing activities of Tiam1 and Bcr. EphBs may regulate Tiam1 and Bcr function by modulating their phosphorylation state, since neuronal EphBs induce phosphorylation of Tiam1 (Tolias et al, 2007) and dephosphorylation of Bcr (Figures S6C–S6E) on sites known to cause GEF activation (Miyamoto et al, 2006) and GAP inhibition (Park et al, 2012), respectively.…”

“…EphB activation triggers the phosphorylation of Tiam1 (Tolias et al, 2007) and the dephosphorylation of Bcr. Phosphorylation of Tiam1 enhances its recruitment to EphB complexes and its Rac-GEF activity (Tolias et al, 2005; Miyamoto et al, 2006; Tolias et al, 2007), whereas dephosphorylation of Bcr may reduce its binding to Tiam1 and its Rac-GAP activity (Park et al, 2012). This coordinated regulation of Tiam1 and Bcr likely contributes to the transient increase in Rac1 activation required for EphB-dependent spine growth.…”

Rich1 negatively regulates the epithelial cell cycle, proliferation and adhesion by CDC42/RAC1-PAK1-Erk1/2 pathway

“…The activity of small G proteins can be regulated by different mechanisms such as posttranslational modifications, guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs) [15][16][17][18][19][20][21]. The Rho GTPase-activating proteins are one of the major classes of regulators found in all eukaryotes, which are crucial in cell cytoskeletal organization [22][23][24][25][26], cycle [27][28][29][30][31], proliferation [32][33][34][35][36][37][38], differentiation [39][40][41], neuronal development [42][43][44][45][46][47] and synaptic functions [48][49][50]. But Rho-family GAPs are more numerous than the GTPases themselves and typically contain interaction domains through which they are directed to specific subcellular compartments and might recruit upstream regulators, downstream effectors and cytoplasmic scaffolds.…”