Functional analysis of the adaptor protein CIN85 and its isoforms in vivo
Final Report Abstract
Cbl-interacting protein of 85 kDa (CIN85) and CD2-associated protein (CD2AP) belong to a family of adaptor molecules implicated in receptor endocytosis, neuronal cell survival, formation of immunological synapse in T cells and kidney filtration functions. Mice lacking CD2AP die of renal failure shortly after birth, whereas CD2AP hyploinsuficiency in humans leads to focal segmental glomerulosclerosis. Transcription of the CIN85 gene is regulated by six promoters scattered throughout the gene locus, in order to gain insights into physiological and pathological roles of CIN85 in vivo, we propose to ablate CIN85 and its multiple isoforms in mice by a gene targeting approach. We were successful in the deletion of individual exons in the CIN85 gene (CIN85-/-Δex2, CIN85 -/-Δex12) and delineated specific functions of CIN85 isoforms present in the brain in vivo. Numerous results point to the functional redundancy between CIN85 and its close homologue CD2AP. Thus, we generated CIN85/CD2AP double knock-out mice and study their overlapping functions during development and adult life of mice. Within this grant we revealed the unique and common functions of CIN85 isoforms in vivo.
Publications
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Aissouni Y, Zapart G, lovanna JL, Dikic I, Soubeyran P. CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Biochem Biophys Res Commun. 2005,338:808-14.
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Dikic I, Schmidt MH. Malfunctions within the Cbl interactome uncouple receptor tyrosine kinases from destructive transport. Eur J Cell Biol. 2007, 86:505-12.
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Haglund K, Schmidt MHH, Wong ESM, Guy GR, Dikic I. Sprouty2 acts at the Cbl/CIN85 interface to inhibit EGFR downregulation. EMBO reports, 2005,6:635-41.
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Jozic D, Cardenes N, Lissanu Deribe Y, Moncaliän G, Hoelter D, Groemping Y, Dikic I*, Rittinger K*, Bravo J*. Cbl promotes clustering of endocytic adaptor proteins. Nat Struct Mol Biol 2005, 12:972 - 9.
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Molfetta R, Belleudi F, Peruzzi G, Morrone S, Leone L, Dikic I, Piccoli M, Frau L, Torrisi MR, Santoni A, Paolini R. CIN85 regulates the ligand-dependent endocytosis of the IgE receptor: a new molecular mechanism to dampen mast cell function. J. Immunol. 2005,175: 4208-16.
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Moncalian G, Cardenes N, Deribe YL, Spinola-Amilibia M, Dikic I, Bravo J. Atypical polyproline recognition by the CMS N-terminal SH3 domain. J Biol Chem. 2006,281:38845-53.
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Sargin B, Choudhary C, Crosetto N, Schmidt MH, Grundler R, Rensinghoff M, Thiessen C, Tickenbrock L, Schwäble J, Brandts C, August B, Koschmieder S, Bandi SR, Duyster J, Berdel WE, Muller-Tidow C, Dikic I, Serve H. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007,110:1004-12.
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Schmidt MH, Husnjak K, Szymkiewicz 1, Haglund K, Dikic I. Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix. Oncogene 2006,25:3071-8.
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Schmidt MHH, Dikic I. Cbl interactome and its functions. Nat Rev Cell Mol Biol. 2005, 6:907-19.
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Schmidt MHH, Dikic I. Methods to monitor EOF receptor degradation. Methods Mol Biol. 2006, 327:131-8.
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Tossidou I, Kardinal C, Peters 1, Kriz W, Shaw A, Dikic I, Tkachuk S, Dumler I, Haller H, Schiffer M. CD2AP/CIN85 balance determines RTK-signaling response in podocytes. J Biol Chem. 2007, 282:7457-64.
