Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatidyl inositol 3-kinase (PI3-kinase) functions as a lipid kinase to produce PI(3,4,5)P(3) from PI(4,5)P(2) in vivo. PI(3,4,5)P(3) is crucial as a lipid second messenger in various metabolic effects of insulin. Lipid phosphatases, src homology 2 domain containing inositol 5'-phosphatase 2 (SHIP2) and skeletal muscle and kidney-enriched inositol phosphatase (SKIP) hydrolyze PI(3,4,5)P(3) to PI(3,4)P(2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) hydrolyzes PI(3,4,5)P(3) to PI(4,5)P(2). SHIP2 negatively regulates insulin signaling relatively specifically via its 5'-phosphatase activity. Targeted disruption of the SHIP2 gene in mice resulted in increased insulin sensitivity and conferred protection from obesity induced by a high-fat diet. Polymorphisms in the human SHIP2 gene are associated, at least in part, with the insulin resistance of type 2 diabetes. Importantly, inhibition of endogenous SHIP2 through the liver-specific expression of a dominant-negative SHIP2 improves glucose metabolism and insulin resistance in diabetic db/db mice. Overexpression of PTEN and SKIP also inhibited insulin-induced phosphorylation of Akt and the uptake of glucose in cultured cells. Although a homozygous disruption of the PTEN gene in mice results in embryonic lethality, either skeletal muscle or adipose tissue-specific disruption of PTEN ameliorated glucose metabolism without formation of tumors in animal models of diabetes. The role of SKIP in glucose metabolism remains to be further clarified in vivo. Taken together, inhibition of endogenous SHIP2 in the whole body appears to be effective at improving the insulin resistance associated with type 2 diabetes and/or obesity. Inhibition of PTEN in the tissues specifically targeted, including skeletal muscle and fat, may result in an amelioration of insulin resistance in type 2 diabetes, although caution against the formation of tumors is needed.
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PMID:Lipid phosphatases as a possible therapeutic target in cases of type 2 diabetes and obesity. 1684 57

Phosphoinositol phosphatases are important regulators of signaling pathways relevant to both diabetes and cancer. A 3'-phosphoinositol phosphatase, phosphatase homologous to tensin (PTEN), is both a tumor suppressor and a negative regulator of insulin action. A 5'-phosphoinositol phosphatase, SH2-containing 5'-inositol phosphatase (SHIP2), regulates insulin signaling and its genetic knockout prevents high-fat diet-induced obesity in mice. SHIP2 also regulates cytoskeleton remodeling and receptor endocytosis. This and the fact that both PTEN and SHIP2 act on the same substrate suggest a potential role for SHIP2 in cancer. Here we report that, in direct contrast to PTEN, SHIP2 protein expression is elevated in a number of breast cancer cell lines. RNA interference-mediated silencing of SHIP2 in MDA-231 cells suppresses epidermal growth factor receptor (EGFR) levels by means of enhanced receptor degradation. Furthermore, endogenous SHIP2 in MDA-231 breast cancer cells supports in vitro cell proliferation, increases cellular sensitivity to drugs targeting the EGFR and supports cancer development and metastasis in nude mice. In addition, significantly high proportions (44%; P = 0.0001) of clinical specimens of breast cancer tissues in comparison with non-cancerous breast tissues contain elevated expression of SHIP2 protein. Taken together, our results demonstrate that SHIP2 is a clinically relevant novel anticancer target that links perturbed metabolism to cancer development.
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PMID:Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. 1789 31

SH2-containing 5'-inositol phosphatase (SHIP2) is a known regulator of insulin function. Genetic knockout of SHIP2 in mice causes mild insulin hypersensitivity and prevents high-fat-diet-induced obesity. SHIP2 also regulates actin remodeling and epidermal growth factor receptor (EGFR) turnover and supports breast cancer; and metastatic growth. To determine the clinical significance of SHIP2 expression in breast cancer and its relationship to relevant oncogenic molecules, SHIP2 expression was determined immunohistochemically in 285 primary breast cancers; 140 ductal carcinomas in situ (DCIS) and 145 invasive carcinomas. Forty-five percent of the specimens showed high SHIP2 levels in cancer cells while only 15% of adjacent normal cells expressed high SHIP2 levels (p < 0.0001). In cancer cells, the risk of SHIP2 overexpression is elevated (a) in women aged < or =50 years (relative risk, RR = 4.13; 95% confidence interval, CI, 2.5-6.9) compared to women aged >50 years (RR = 2.37; 95% CI 1.6-3.5; p = 0.0003), and (b) in invasive carcinomas (RR = 3.52; 95% CI 2.3-5.5) compared with DCIS (RR = 2.22; 95% CI 1.5-3.5; p = 0.0009). Patients with higher SHIP2 levels in invasive carcinomas had significantly reduced disease-free (p = 0.0025) and overall survival periods (p = 0.0228). In invasive carcinomas, SHIP2 correlated with estrogen receptor absence (p = 0.003) and EGFR presence (p = 0.0147). In conclusion, SHIP2 is an important biomarker for breast cancer.
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PMID:High expression of obesity-linked phosphatase SHIP2 in invasive breast cancer correlates with reduced disease-free survival. 1906 64

The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia. This review focuses on the mutations associated with opsismodysplasia and explores the role of INPPL1/ SHIP2 in skeletal development.
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PMID:INPPL1 gene mutations in opsismodysplasia. 2770 70