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Molecular and Cellular Biology, April 2001, p. 2767-2778, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2767-2778.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Intermolecular and Intramolecular Interactions Regulate Catalytic Activity of Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinase alpha

Ivan Tan,1 Kah Tong Seow,1 Louis Lim,1,2 and Thomas Leung1,*

Glaxo-IMCB Group, Institute of Molecular & Cell Biology, Singapore 117609, Singapore,1 and Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom2

Received 5 October 2000/Returned for modification 3 November 2000/Accepted 31 January 2001

Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) is a Cdc42-binding serine/threonine kinase with multiple functional domains. We had previously shown MRCKalpha to be implicated in Cdc42-mediated peripheral actin formation and neurite outgrowth in HeLa and PC12 cells, respectively. Here we demonstrate that native MRCK exists in high-molecular-weight complexes. We further show that the three independent coiled-coil (CC) domains and the N-terminal region preceding the kinase domain are responsible for intermolecular interactions leading to MRCKalpha multimerization. N terminus-mediated dimerization and consequent transautophosphorylation are critical processes regulating MRCKalpha catalytic activities. A region containing the two distal CC domains (CC2 and CC3; residues 658 to 930) was found to interact intramolecularly with the kinase domain and negatively regulates its activity. Its deletion also resulted in an active kinase, confirming a negative autoregulatory role. We provide evidence that the N terminus-mediated dimerization and activation of MRCK and the negative autoregulatory kinase-distal CC interaction are two mutually exclusive events that tightly regulate the catalytic state of the kinase. Disruption of this interaction by a mutant kinase domain resulted in increased kinase activity. MRCK kinase activity was also elevated when cells were treated with phorbol ester, which can interact directly with a cysteine-rich domain next to the distal CC domain. We therefore suggest that binding of phorbol ester to MRCK releases its autoinhibition, allowing N-terminal dimerization and subsequent kinase activation.

* Corresponding author. Mailing address: Glaxo-IMCB Group, Institute of Molecular & Cell Biology, 30 Medical Dr., Singapore 117609, Singapore. Phone: (65) 874 6167. Fax: (65) 774 0742. E-mail: mcbthoml{at}imcb.nus.edu.sg.

Molecular and Cellular Biology, April 2001, p. 2767-2778, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2767-2778.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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