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Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization

Philippe Grimbert¹, Asta Valanciute¹, Vincent Audard¹, André Pawlak¹, Sabine Le gouvelo¹, Philippe Lang², Patrick Niaudet³, Albert Bensman⁴, Georges Guellaën¹ and Djillali Sahali¹

¹ Unité INSERM 99, Hôpital Henri Mondor, AP-HP, Université Paris XII, 94010 Créteil, France
² Service de néphrologie adulte, Hôpital Henri Mondor, AP-HP, Université Paris XII, 94010 Créteil, France
³ Service de néphrologie, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France
⁴ Service de néphrologie, Hôpital Armand Trousseau, AP-HP, 75012 Paris, France

Address correspondence to D. Sahali, Unité INSERM 99, Hôpital Henri Mondor, 51, avenue du Mal de Lattre-de-Tassigny, 94010 Créteil, France. Phone: 33-1-49 81 35 30; Fax: 33-1-48 98 09 08; email: sahali{at}im3.inserm.fr

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH₂-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4⁺ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

Key Words: lipoid nephrosis • T lymphocytes • pleckstrin domain • signal transduction

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