Other names: SHIP2 (SH2-containing 5'-inositol phosphatase 2)/SHIP-2, 51C

Disease relevance of INPPL1

• INPPL1 mutations affecting gene function have been found in rat models of type 2 diabetes and hypertension and in type 2 diabetic patients [1].
• SHIP2 protein is expressed at higher levels in cancer cell lines as compared to non-trasnformed cells and in human breast cancer tissues as compared to normal breast tissues[2]
• SHIP2 protein expression in invasive breast cancers positively correlates with reduced disease-free survival and estrogen receptor (ER)-negative and epidermal growth factor receptor (EGFR)-positive status [3]

High impact information on INPPL1

• We have found highly significant associations of single nucleotide polymorphisms (SNPs) and haplotypes of INPPL1 with hypertension as well as with other components of the metabolic syndrome [1].
• Type II SH2 domain-containing inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity [1].
• Silencing of endogenously overexpresed SHIP2 in invasive breast cancer cells decreases in vitro cell proliferation and suppresses tumor growth and spontaneous lung metastases in nude mouse orthotopic mammary fatpad xenograft studies [2]
• Endogenously overexpressed SHIP2 in breast cancer cells, by inihibiting EGF-induced EGFR endocytosis and subsequent receptor downregulation, promotes EGFR-Akt signaling, CXCR4 expression and cancer cell migration [4]
• Our results validate SHIP2 as a novel anti-cancer drug target  
• Expression of SHIP2 promotes invadopodia formation by Phosphoinositol 3-kinase in cancer cells [5]

Biological context of INPPL1

• SHIP2 is tyrosine phosphorylated in response to growth factors and insulin and associates with SHC adapter protein [6]
• We found that SHIP2 interacts with adhesion protein p130^Cas via its SH2-domain. Although diffusely present in the cytoplasm, SHIP2 localizes to focal contact points and to lamellipodia structures during cell spreading and SH2-domain is important for this localization. Catalytic activity of SHIP2 plays an important role in cell spreading [7]
• SHIP2 is tyrosine phosphorylated during cell spreading on type I collagen (but not on other matrix proteins) by Src family kinases. This phosprylation of NPXY motif is critical for SHIP2-SHC interaction and for lamellipodia formation [8]
• SHIP2 suppresses EGF-induced endocytosis and downregulation of EGFR by reducing EGFR-c-Cbl association and EGFR ubiquitination [9].
• We observed that SHIP2 constitutively associates with c-Cbl in cervical and breast cancer cells [9] [2]
• In a cohort of 905 French type 2 diabetic patients, we found evidence of association of INPPL1 SNPs with the presence of hypertension [1].
• Tyrosine phosphorylation was shown to enhance SHIP2 phosphatase activity [10].
• In this report, we show that tyrosines 986-987 and 1135 are critical for EGF-induced stimulation of SHIP2 activity. SHIP2 with a disrupted SH2-domain (R47G mutation) displays higher constitutive activity than the wild-type SHIP2. Deletion of the C-terminus region similarly activates SHIP2. Thus, SH2-domain of SHIP2, in conjunction with the C-terminus, confers an inhibitory effect to maintain a low basal activity and signal-induced tyrosine phosphorylations overcome this effect to activate SHIP2 [11].

Analytical, diagnostic and therapeutic context of INPPL1 INPPL1

• One of the PCR fragment referred to as 51 C, shows 99% identity to a previously reported sequence (INPPL-1) present in the database [12].
• SHIP2 expression analysis of human breast cancer is a prognostic marker of aggressive disease outcome and it may also be useful as a diagnsotic marker of cancer predisposition [3]
• SHIP2 in breast cancer cells regulates EGFR expression levels. Targeted suppression of SHIP2 enhances cellular sensitivity to anti-EGFR drugs [2]

References