Structure, function, and biology of SHIP proteins

One of the “simple” curiosities of life, at least for a biological scientist, is how the growth and development of a complete organism from a single cell is controlled. Part of the answer includes growth factor receptors and their respective ligands, which transduce signals across cell membranes and into the nucleus for transcriptional readout. The molecular nature of these intracellular signals determines the type of signals, the pathways involved, subsequent regulatory interactions, and eventual transcription factor activation/repression. Hematopoietic cell development has been a fruitful system for the analysis of these signals because mature blood cells develop from a small population of self-replicating stem cells in the bone marrow, providing a convenient model cell system to study these mechanisms. In recent years a new signaling protein component of many growth factor receptor signaling pathways has been identified, called SHIP (SH2-containingInositol 5′-Phosphatase). This review presents current structural information on the SHIP protein and its various roles in cellular regulation.

SHIP was initially observed as a tyrosine-phosphorylated protein after stimulation of blood cells by any of a broad number of cytokines and growth factors (Damen et al. 1993; Kavanaugh and Williams 1994; Lioubin et al. 1994; Liu et al. 1994; Matsuguchi et al. 1994; Saxton et al. 1994; Drachman et al. 1995; Chacko et al. 1996; Crowley et al. 1996). cDNAs for the cognate protein were cloned by several laboratories. The cloning methods varied, and some utilized the biochemically identified interactions of SHIP with Grb2, Shc, or Fc receptors to isolate a ∼145-kD protein, obtain peptide sequences, and screen a cDNA library with degenerate probes (Damen et al. 1996; Kavanaugh et al. 1996; Ono et al. 1996; Odai et al. 1997). A novel approach employing a modified …