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J. Biol. Chem., Vol. 283, Issue 44, 30246-30255, October 31, 2008

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Goodpasture Antigen-binding Protein Is a Soluble Exportable Protein That Interacts with Type IV Collagen

IDENTIFICATION OF NOVEL MEMBRANE-BOUND ISOFORMS^*

Fernando Revert, Ignacio Ventura, Pilar Martínez-Martínez, Froilán Granero-Moltó, Francisco Revert-Ros, Jesús Macías, and Juan Saus¹

From the Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain and the Departamento de Bioquímica y Biología Molecular, Universitat de Valencia, 46010 Valencia, Spain

Goodpasture-antigen binding protein (GPBP) is a nonconventional Ser/Thr kinase for basement membrane type IV collagen. Various studies have questioned these findings and proposed that GPBP serves as transporter of ceramide between the endoplasmic reticulum and the Golgi apparatus. Here we show that cells expressed at least two GPBP isoforms resulting from canonical (77-kDa) and noncanonical (91-kDa) mRNA translation initiation. The 77-kDa polypeptide interacted with type IV collagen and localized as a soluble form in the extracellular compartment. The 91-kDa polypeptide and its derived 120-kDa polypeptide associated with cellular membranes and regulated the extracellular levels of the 77-kDa polypeptide. A short motif containing two phenylalanines in an acidic tract and the 26-residue Ser-rich region were required for efficient 77-kDa polypeptide secretion. Removal of the 26-residue Ser-rich region by alternative exon splicing rendered the protein cytosolic and sensitive to the reduction of sphingomyelin cellular levels. These and previous data implicate GPBPs in a multicompartmental program for protein secretion (i.e. type IV collagen) that includes: 1) phosphorylation and regulation of protein molecular/supramolecular organization and 2) interorganelle ceramide trafficking and regulation of protein cargo transport to the plasma membrane.

Received for publication, July 2, 2008 , and in revised form, August 1, 2008.

^* This work was supported by Grants SAF97/0065, SAF2000/0047, SAF2001/0453, SAF2003-09772-C03-01, and SAF2006-12520-C02-01 from Ministerio de Educación y Ciencia, Grant 98/102-00 from Fundación "La Caixa," and Grants GV04B-285 and BM-001/2002 from Generalitat Valenciana (Spain) (to J. S.). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Centro de Investigación Príncipe Felipe, Avda. Autopista del Saler 16, 46012 Valencia, Spain. Tel.: 34-96-3289680; Fax: 34-96-3289701; E-mail: jsaus{at}cipf.es.

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