Cdk5 is a unique member of the cyclin-dependent kinase (Cdk) family of proline-directed Ser/Thr protein kinases. In conjunction with its neuron-specific activator p35, Cdk5 plays an essential role in the development of the central nervous system. Mice lacking Cdk5 or p35 display disrupted lamination patterns of the cerebral cortex, indicating impairment in neuronal migration. It has been known that actin repolymerization plays a crucial role in cell morphogenesis and migration. The immunoreactivity of Cdk5 and p35 is found in n regions rich in filamentous actin,, such as the leading edge of growth cones, implying a role of Cdk5 and p35 in the regulation of the actin cytoskeleton during neuronal migration....[ Read more ]

Cdk5 is a unique member of the cyclin-dependent kinase (Cdk) family of proline-directed Ser/Thr protein kinases. In conjunction with its neuron-specific activator p35, Cdk5 plays an essential role in the development of the central nervous system. Mice lacking Cdk5 or p35 display disrupted lamination patterns of the cerebral cortex, indicating impairment in neuronal migration. It has been known that actin repolymerization plays a crucial role in cell morphogenesis and migration. The immunoreactivity of Cdk5 and p35 is found in n regions rich in filamentous actin,, such as the leading edge of growth cones, implying a role of Cdk5 and p35 in the regulation of the actin cytoskeleton during neuronal migration.

In the present study, we have found a novel role for p35 as an actin-binding protein that polymerizes and bundles actin. Actin exists in the forms of monomeric actin (G-actin) and filamentous actin (F-actin). Protein binding assays show that p35 interacts with both G-actin and F-actin. Further, p35 assembles G-actin into F-actin in a mechanism that is distinct from those of known actin-polymerizing proteins in animals. Expression of p35 in transfected cells induces the formation of actin filaments, which are decorated with p35 along the fibers. Further, the p35 expression significantly reduces actin stress fibers, consistent with its role in cell movement. Cdk5-p35 has been shown to phosphorylate PAK (p21-activated kinase), mediating the actin cytoskeletal organization. We investigated the involvement of Cdk5 in p35-mediated actin dynamics. Interestingly, the actin-polymerizing and bundling activity of p35 does not depend on its association with Cdk5. Rac, a member of the Rho family of GTPases, is a key regulator of the actin meshwork at the cell periphery and induces the formation of lamellipodia and membrane ruffles when exists in the active form (GTP-bound). We have found that active Rac physically associates with p35, recruiting p35 as well as Cdk5 to the cell periphery. Taken together, p35 regulates the actin organization for neurite outgrowth and neuronal migration at least in two ways; one is the direct actin assembly and bundling; another is the phosphorylation of PAK through the activation of Cdk5. These Cdk5 and p35 actions are controlled by the Rac GTPase system. Our studies have provided new molecular insights of neuronal migration and differentiation.