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J. Biol. Chem., Vol. 278, Issue 36, 34181-34188, September 5, 2003

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CRIM1 Regulates the Rate of Processing and Delivery of Bone Morphogenetic Proteins to the Cell Surface^*

Lorine Wilkinson , Gabriel Kolle   ¶, Daying Wen , Michael Piper , Julie Scott  and Melissa Little  ||

From the Institute for Molecular Bioscience and the Department of Biochemistry, The University of Queensland, Brisbane, Queensland 4072, Australia

The Crim1 gene is predicted to encode a transmembrane protein containing six von Willebrand-like cysteine-rich repeats (CRRs) similar to those in the BMP-binding antagonist Chordin (Chrd). In this study, we verify that CRIM1 is a glycosylated, Type I transmembrane protein and demonstrate that the extracellular CRR-containing domain can also be secreted, presumably via processing at the membrane. We have previously demonstrated Crim1 expression at sites consistent with an interaction with bone morphogenetic proteins (BMPs). Here we show that CRIM1 can interact with both BMP4 and BMP7 via the CRR-containing portion of the protein and in so doing acts as an antagonist in three ways. CRIM1 binding of BMP4 and -7 occurs when these proteins are co-expressed within the Golgi compartment of the cell and leads to (i) a reduction in the production and processing of preprotein to mature BMP, (ii) tethering of pre-BMP to the cell surface, and (iii) an effective reduction in the secretion of mature BMP. Functional antagonism was verified by examining the effect of co-expression of CRIM1 and BMP4 on metanephric explant culture. The presence of CRIM1 reduced the effective BMP4 concentration of the media, thereby acting as a BMP4 antagonist. Hence, CRIM1 modulates BMP activity by affecting its processing and delivery to the cell surface.

Received for publication, February 5, 2003 , and in revised form, June 10, 2003.

In memory of our colleague Dr. Toshiya Yamada, 1960–2001.

^* This work was supported in part by the National Health and Medical Research Council (NMHRC) of Australia (Grant 102578) and the Sylvia and Charles Viertel Charitable Trust. 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.

^¶ Holds an Australian Postgraduate Award.

^|| An NHMRC Senior Research Fellow and a Sylvia and Charles Viertel Senior Research Fellow. To whom correspondence should be addressed. Tel.: 61-7-3365-4494 (ext. 1819); Fax: 61-7-3365-4388; E-mail: M.Little{at}imb.uq.edu.au.

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