Phosphoinositides and human diseases

As described above, phosphoinositides control many different processes required for normal cellular function. Thus, it is not surprising that dysfunctions in the control of their levels lead to pathologies. Indeed, recent discoveries have brought phosphoinositide-metabolizing enzymes to the forefront of biomedical research. Several phosphoinositide kinases and phosphatases are clearly implicated in the development of human diseases, as briefly summarized below. 

Recently, a somatic mutation of another PtdIns(3,4,5)P3-phosphatase, the 5-phosphatase SHIPl, was reported in primary myeloid leukemia cells (Luo et al, 2003). This mutation, in the phosphatase active site (V684E), generates a mutant catalytically defective in PtdIns(3,4,5)Pj 5-phosphatase activity. The consequences are enhanced Akt phosphorylation in response to interleukin-3, promotion of cell survival under conditions of serum deprivation, and resistance to apoptosis. Thus, mutations of the SHIPl gene may be involved in the development of acute leukemia and chemotherapy resistance through deregulation of the PtdIns(3,4,5)P3/Akt signalling pathway. 

The gene mutated in X-linked myotubular myopathy (XLMTM), a severe congenital disorder characterized by generalized muscle weakness and hypotonia, codes for a ubiquitously expressed protein, myotubularin. This protein presents the conserved sequence of the phosphotyrosine phosphatase s active site. However, studies of its substrate specificity have shown that myotubularin s preferred substrates are PtdIns(3)P and Ptdlns(3,5)P2 (Blondeau et al, 2000 Schaletzky et al, 2003). Accordingly, it has been shown that 

Another example of a bacterial pathogen using phosphoinositide metabolism to enter host cells is the Gram-negative bacillus Shigella flexnerl Shigella injects, by its type III secretion system, a protein, IpgD, which has two 

Anderson, RA, Boronenkov, IV, Donghman, SD, Kunz, J and Loijens, JC (1999) Phosphatidylinositol phosphate kinases, a mnltifaced family of signahng enzymes. J Biol Chem, TIA, 9907-9910. 

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