The Kinase Activity of Cdk5 and Its Regulation

Abstract

Cdk5 is a member of cyclin-dependent kinase (Cdk) family and is uniquely activated by binding to its neuron-specific non-cyclin activator p35 or p39. In this chapter we describe the enzymatic properties and the regulation mechanisms of Cdk5 activity in post-mitotic neurons in comparison to cell cycle Cdks. The regulation mechanisms are synthesis and degradation of p35, the interaction with p35-or Cdk5-binding proteins, phosphorylation of Cdk5 or p35, and the association with membranes. In addition to these physiological regulations, deregulation of the activity is induced by the cleavage of p35 to p25 by calpain, leading to hyperactivation and eventually neuronal cell death. The kinase activity and stability of Cdk5-p39, which still remains to be characterized, are also described here. The biochemical information will be useful in studying Cdk5 and elucidating its functions.

Extracellular alpha‐synuclein induces calpain‐dependent overactivation of cyclin‐dependent kinase 5 in vitro

“…Moreover, we observed an alternative mechanism of Cdk5 activation by enhanced phosphorylation of this enzyme at Tyr15 in the ASN‐treated cells. Several kinases (Fyn, c‐Abl, TrkB, Eph4, HER2 and FGFR1) and protein phosphatase 1 are responsible for regulation of Cdk5 phosphorylation at this site [32,41,27,18]. Therefore, the exact mechanism responsible for this phenomenon needs further investigation.…”

Alterations of Cyclin dependent kinase 5 expression and phosphorylation in Amyloid precursor protein (APP)-transfected PC12 cells

“…Several kinases may be responsible for Cdk5 phosphorylation. Fyn, c‐Abl, TrkB, Eph4, HER2 and FGFR1 are upstream Cdk5 kinases responsible for Tyr15 phosphorylation [34–37]. Also, Protein phosphatase 1 is responsible for Tyr15 site regulation [36].…”