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J. Biol. Chem., Vol. 279, Issue 23, 23863-23868, June 4, 2004
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Tissue Transglutaminase Has Intrinsic Kinase Activity
IDENTIFICATION OF TRANSGLUTAMINASE 2 AS AN INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3 KINASE*
¶
From the
Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg R3E 0W3, Canada
Tissue transglutaminase (TG2) is a ubiquitous enzyme that cross-links glutamine residues with lysine residues, resulting in protein polymerization, cross-linking of dissimilar proteins, and incorporation of diamines and polyamines into proteins. It has not previously been known to have kinase activity. Recently, insulin-like growth factor-binding protein-3 (IGFBP-3) has been reported to be phosphorylated by breast cancer cell membranes. We purified the IGFBP-3 kinase activity from solubilized T47D breast cancer cell membranes using gel filtration, ion-exchange chromatography, and IGFBP-3 affinity chromatography. The fractions containing kinase activity were further purified by high pressure liquid chromatography and analyzed by tandem mass spectroscopy. TG2 was detected in fractions containing kinase activity. Antisera to TG2 and protein A-Sepharose were used to immunoprecipitate TG2 from membrane fractions. The immunoprecipitates retained IGFBP-3 kinase, whereas immunoprecipitation deleted kinase activity in the membrane supernatant. The inhibitors of TG2, cystamine and monodansyl cadaverine, abolished the ability of the T47D cell membrane preparation to phosphorylate IGFBP-3. Both TG2 purified from guinea pig liver and recombinant human TG2 expressed in insect cells were able to phosphorylate IGFBP-3. TG2 kinase activity was inhibited in a concentration-dependent fashion by calcium, which has previously been shown to be important for the cross-linking activity of TG2. These data provide compelling evidence that TG2 has intrinsic kinase activity, a function that has not previously been ascribed to TG2. Furthermore, we provide evidence that TG2 is a major component of the IGFBP-3 kinase activity present on breast cancer cell membranes.
Received for publication, October 30, 2003 , and in revised form, March 15, 2004.
* This work was supported by a grant from the Canadian Institutes for Health Research (CIHR). 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.
¶ Recipient of a CIHR Senior Scientist award and the Henry G. Friesen Research Professorship in Metabolic Diseases. To whom correspondence should be addressed: Rm. 843, John Buhler Research Centre, University of Manitoba, 715 McDermot Ave., Winnipeg MB R3E 3P4, Canada. Tel.: 204-789-3779; Fax: 204-789-3940; E-mail: ljmurph{at}cc.umanitoba.ca.
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