Role of G-protein coupled receptor kinase interacting protein 1 (GIT1) in bone homeostasis and brain development

G-protein coupled receptor kinase interacting protein-1 (GIT1) was identified as a 97-kd protein tyrosine phosphorylated by c-Src upon angiotension II (Ang II) stimulation in vascular smooth muscle cells (VSMC). GIT1 plays a key role in cytoskeleton dynamics, membrane trafficking and in recycling endosomes. Since GIT1 regulates cytoskeleton dynamics, we hypothesized that, deletion of GIT1 might perturb osteoclast function and bone homeostasis. Bone morphometric analyses show that GIT1 KO mice have a 2.3 fold increase in hone density compared to WT controls. Osteoclasts cultured from bone marrow cells of GIT1 KO were not able to form podosome belts at the cell periphery resulting in decreased bone resorbtion and impaired osteoclast function in comparison to WT. Furthermore we demonstrate that GIT1 is tyrosine phosphorylated upon RANK stimulation, interacts with RANK receptor and is required for PLCgamma2 phosphorylation in osteoclasts. Thus we demonstrate that GIT1 regulates bone density in vivo through effects on RANK-PLCgamma2 required for podosome belt formation in osteoclasts.;GIT1 is highly expressed in the brain. In vitro data have shown it to be important for spine (actin rich protrusiosn) and synapse formation in the brain. These processes are dependent on actin cytoskeleton organization. Hence we hypothesized that deletion of GIT1 might affect these process, which are known to be important for learning and memory. GIT1 KO mice showed markedly reduced dendritic length and spine density in the hippocampus by 36.7% and 35.1% respectively. This correlated with their poor adaptation to new environments as shown by impaired performance on tasks dependent on learning. We also studied the effect of GIT1 gene deletion on brain microcirculation. In contrast to findings in systemic circulation, GIT1 KO mice had an intact blood-brain barrier and normal regional cerebral blood flow as determined with radiotracers. Thus, our data suggest that GIT1 plays an important role in brain in vivo by regulating spine density involved in synaptic plasticity that is required for processes involved in learning.;In conclusion, we show novel roles of GIT1, a multi-domain scaffold protein in bone homeostasis and for cognition in the brain by regulating process dependent on actin cytoskeleton dynamics.