HIKE is a highly conserved sequence motif identified as a candidate
pleckstrin-homology (PH) domain binding site in Gbeta
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 Gbeta,
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.