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Human Molecular Genetics, 2000, Vol. 9, No. 6 1001-1007
© 2000 Oxford University Press

Large and diverse numbers of human diseases with HIKE mutations

Francesca D. Ciccarelli, Angela Acciarito and Saverio Alberti+

Laboratory of Experimental Oncology, Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche Mario Negri—Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy

HIKE is a highly conserved sequence motif identified as a candidate pleckstrin-homology (PH) domain binding site in Gß proteins, protein kinases, ankyrin and kinesin. HIKE motifs occur also in gelsolin, neurogranin, neuromodulin and in the PH domain of Bruton tyrosin kinase (BTK). Phosphatidylinositol-binding sequences more distantly related to HIKE are present in gelsolin, in the G protein-coupled receptor kinase 4 and in Trop-2. HIKE regions have been demonstrated to bind both proteins and lipids, and to regulate the interaction of Gß, neuromodulin and the BTK PH domain with downstream effectors and the cell membrane. Remarkably, mutations of the HIKE regions are common in diverse human genetic diseases. Several HIKE mutations in protein kinases lead to constitutive activation and cellular transformation, e.g. in MEN-2B, acute myeloid and mast cell leukemias, hereditary papillary renal carcinomas and multiple myeloma. Kinase-inactivating HIKE mutations cause Hirschsprung’s disease, piebaldism, insulin resistance and developmental dysplasias. HIKE mutations in the PH domain of BTK lead to X-linked agammaglobulinemia, and different forms of amyloidosis are caused by mutations of HIKE-bearing molecules, for example gelsolin, Ret and Trop-2. Thus, quite diverse genetic diseases might share common molecular mechanisms. These include altered interactions of the mutated molecules with downstream effectors or the cell membrane, and defects in intracellular transport.

+ To whom correspondence should be addressed. Tel: +39 0872 570 293; Fax: +39 0872 578 240; Email: alberti@cmns.mnegri.it


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