Regulation of microfilament organization by Kaposi sarcoma-associated herpes virus-cyclin·CDK6 phosphorylation of caldesmon

Maria Emanuela Cuomo, Axel Knebel, Georgina Platt, Nick Morrice, Philip Cohen, Sibylle Mittnacht (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Kaposi sarcoma-associated herpes virus (KSHV) encodes a D-like cyclin (K-cyclin) that is thought to contribute to the viral oncogenicity. K-cyclin activates cellular cyclin-dependent kinases (CDK) 4 and 6, generating enzymes with a substrate selectivity deviant from CDK4 and CDK6 activated by D-type cyclins, suggesting different biochemical and biological functions. Here we report the identification of the actin- and calmodulin-binding protein caldesmon (CALD1) as a novel K-cyclin·CDK substrate, which is not phosphorylated by D·CDK. CALD1 plays a central role in the regulation of microfilament organization, consequently controlling cell shape, adhesion, cytokinesis and motility. K-cyclin·CDK6 specifically phosphorylates four Ser/Thr sites in the human CALD1 carboxyl terminus, abolishing CALD1 binding to its effector protein, actin, and its regulator protein, calmodulin. CALD1 is hyperphosphorylated in cells following K-cyclin expression and in KSHV-transformed lymphoma cells. Moreover, expression of exogenous K-cyclin results in microfilament loss and changes in cell morphology; both effects are reliant on CDK catalysis and can be reversed by the expression of a phosphorylation defective CALD1. Together, these data strongly suggest that K-cyclin expression modulates the activity of caldesmon and through this the microfilament functions in cells. These results establish a novel link between KSHV infection and the regulation of the actin cytoskeleton.

Original languageEnglish
Pages (from-to)35844-35858
Number of pages15
JournalJournal of Biological Chemistry
Volume280
Issue number43
DOIs
Publication statusPublished - 28 Oct 2005

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