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J. Biol. Chem., Vol. 279, Issue 52, 54387-54397, December 24, 2004

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Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINK^*

Yuanming Hu, Cindy Leo, Simon Yu, Betty C. B. Huang, Hank Wang, Mary Shen, Ying Luo, Sarkiz Daniel-Issakani, Donald G. Payan, and Xiang Xu

From the Rigel Pharmaceuticals, Inc., South San Francisco, California 94080

Misshapen/NIKs-related kinase (MINK) is a member of the germinal center family of kinases that are homologous to the yeast sterile 20 (Ste20) kinases and regulate a wide variety of cellular processes, including cell morphology, cytoskeletal rearrangement, and survival. Here, we present the cloning and functional characterization of a novel human Misshapen/NIKs-related kinase (hMINK) that encodes a polypeptide of 1312 amino acids. hMINK is ubiquitously expressed in most tissues with at least five alternatively spliced isoforms. Similar to Nck interacting kinase (NIK) and Traf2 and Nck-interacting kinase (TNIK), hMINK moderately activates c-Jun N-terminal kinase (JNK) and associates with Nck via the intermediate domain in the yeast two-hybrid system and in a glutathione S-transferase (GST) pull-down assay. Interestingly, overexpression of the kinase domain deleted and kinase-inactive mutants of hMINK in human fibrosarcoma HT1080 cells enhanced cell spreading, actin stress fiber formation, and adhesion to extracellular matrix, as well as decreased cell motility and cell invasion. Furthermore, these mutants also promoted cell-cell adhesion in human breast carcinoma MCF7 cells, evidenced with cell growth in clusters and increased membrane localization of -catenin, a multifunctional protein involved in E-cadherin-mediated cell adhesion. Finally, hMINK protein was found to colocalize with the Golgi apparatus, implicating that hMINK might exert its functions, at least in part, through the modulation of intracellular protein transport. Taken together, these results suggest that hMINK plays an important role in cytoskeleton reorganization, cell adhesion, and cell motility.

Received for publication, April 23, 2004 , and in revised form, September 17, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY775058.

To whom correspondence should be addressed. Tel.: 650-624-1173; Fax: 650-624-1101; E-mail: xxu{at}rigel.com.

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