INPPL1 (inositol polyphosphate phosphatase-like 1)

2009-06-01   Nagendra K Prasad 

Purdue Cancer Center, Purdue Oncological Sciences Center, Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana 47907, USA





The cDNA sequence for human SHIP2 is 3777 nucleotide long (full processed mRNA is 4733 ntd long) (Hejna et al., 1995; Pesesse et al., 1997). The coding region comprises 28 exons. There is evidence for the existence of a shorter transcript (372 ntd long of unknown significance coding for 123 amino acids. The C-terminus 74 codons (including the SAM-domain) are common for both the transcripts.


SHIP2 promoter is regulated by Sp1 transcription factors (Ishida et al., 2005). Mechanisms of transcriptional regulations are unknown and perhaps not present. SHIP2 mRNA is expressed ubiquitously at high levels (Pesesse et al., 1997; Habib et al., 1998) and the protein levels are regulated post-transcriptionally by microRNA-205 (inhibitory) or microRNA-184 (which is a suppressor of mir-205) (Yu et al., 2008).


Atlas Image
Structural features of SHIP2 protein: The positions of the SHIP2 catalytic domain and the protein interaction motifs are shown. Currently known SHIP2-interacting proteins are listed under the respective interaction domain/motifs. SH2 (src homology-2 domain), IPPc (inositol polyphosphate phosphatase catalytic domain), Pro-rich (proline rich region), SAM (sterile alpha-motif).


SHIP2 protein (1258 amino acids long) contains an inositol polyphosphate phosphatase domain (IPPc; aa 422-735). In addition, SHIP2 has an amino-terminal SH2-domain (aa 21-117) and a carboxyl-terminal proline-rich region (Pro-rich; aa 935-1105). Also, SHIP2 contains a NPXY motif (aa 983-986) and a SAM (sterile alpha-motif) domain (aa 1201-1258). These structural elements provide sites for protein-protein interactions which seem to play a major role in SHIP2 function. Several cellular proteins associate with SHIP2 via phosphotyrosine-dependent (SH2 or NPXY mediated) or proline-rich region (SH3 mediated) interactions (for a comprehensive list of interacting proteins and citations please see Prasad, 2009a).


Ubiquitously expressed with higher levels of mRNA in skeletal muscle, liver, adipose tissue, placenta and brain (Pesesse et al., 1997; Habib et al., 1998; Muraille et al., 2001). Also expressed in B-cells, T-cells, platelets, mast cells and macrophages (Muraille et al., 1999; Dyson et al., 2003; Giuriato et al., 2003; Ai et al., 2006; Leung and Bolland, 2007). Protein levels are very low in normal tissues and cells. Higher levels of protein expression is noted in many types of cancer cells (Wisniewski et al., 1999; Prasad et al., 2001; Prasad and Decker 2005) and in human breast cancer tissues (Prasad et al., 2008). SHIP2 protein levels in skeletal muscle and fat are higher in obese db/db mice as compared to normal heterozygous (db/+) mice and SHIP2 protein levels are moderately increased in response to a high-fat diet in normal mice (Hori et al., 2002). SHIP2 genetic sequence in diabetic rats and humans contain mutations that may lead to increased levels of SHIP2 (Marion et al., 2002).


SHIP2 is diffusely cytoplasmic but membrane enrichment of SHIP2 occurs during cell attachment (Prasad et al., 2001), membrane ruffling (Dyson et al., 2001) or in response to m-CSF in macrophages (Wang et al., 2004). Mutation in the SH2-domain (R47G) causes punctate distribution pattern in the cytoplasm of HeLa cells (Prasad et al., 2001). SHIP2 has also been reported to localize to the nuclear speckles in vascular smooth muscle cells (Deleris et al., 2003).


Overview. Phosphoinositide (PI) lipids are important second messengers in the intracellular signaling pathways. PI lipids interact with the pleckstrin homology domain (PH-domain) containing cellular enzymes causing their membrane recruitment and/or allosteric activation. Phosphoinositide 3-kinase (PI3-kinase) is central to the signal-induced generation of new phosphoinositides and its activation is a key intermediate step in the signaling initiated by various external signals including many hormones (insulin and leptin), growth factors (EGF, IGF-1 and PDGF) as well as integrin ligation. SHIP2 dephosphorylates the 5-position of phosphatidylinositol-3,4,5-trisphosphate (PIP3) generated by the PI3-kinase, producing a new second messenger PI-3,4-bisphosphate (PI-3,4-P2). As PI3-kinase pathway aberrations play a major role in the development of cancer, diabetes and inflammation, SHIP2 function is expected to be critically important for the molecular pathogenesis of these diseases. SHIP2 also dephosphorylates PI-3,4-bisphosphate (Taylor et al., 2000). In vitro, a soluble inositol molecule, inositol-1,3,4,5-tetrakisphosphate (IP4) also serves as a high affinity substrate for SHIP2 (Pesesse et al., 1998; Chi et al., 2004; Batty et al., 2007).

Negative Regulator of insulin signaling. In cell culture overexpression studies, SHIP2 acts a mild suppressor of insulin signaling (Sasaoka et al., 2001; Wada et al., 2001). RNA interference studies, however, contradict these observations (Zhou et al., 2004; Huard et al., 2007). SHIP2 null-mice are viable but resistant to high-fat-diet-induced obesity (Sleeman et al., 2005). Insulin signaling was enhanced only modestly in these mice. However, liver-specific suppression of SHIP2 function in mice improves insulin function (Fukui et al., 2005; Grempler et al., 2007). Mechanisms by which SHIP2 achieves the energy homeostasis therefore remain unclear at present.

Negative Regulator of IGF-1 signaling. Exogenous SHIP2 in C2C12 skeletal muscle cells is shown to suppress IGF-1 signaling and to interfere with IGF-1-induced muscle hypertrophy (Rommel et al., 2001). Similarly SHIP2 blocks compensatory hypertrophy upon its exogenous expression in rat skeletal muscle myocytes (Bodine et al., 2001).

Positive Regulator of cytoskeleton remodeling, cell adhesion, lamellipodia formation/cell spreading. Transient exogenous expression of the wild type-SHIP2 increases cellular adhesion in SH2-domain dependent manner in HeLa cells (Prasad et al., 2001). Furthermore, catalytic activity of SHIP2 is important for efficient lamellipodia formation and cell spreading (Prasad et al., 2001). Interaction with c-Met is important for this function of SHIP2 in MDCK cells (Koch et al., 2005). Also, C-terminus proline-rich region of SHIP2 is shown to be important for membrane ruffling process through its interaction with Filamin (Dyson et al., 2003). Src kinase-induced tyrosine phosphorylation of SHIP2 and consequent SHIP2-Shc association are important for HeLa cell spreading on type I collagen (Prasad et al., 2002). In MDA-231 breast cancer cells, SHIP2 promotes cell migration and this effect is associated to sustained EGFR-Akt signaling and increased expression of chemokine receptor CXCR4 (Prasad, 2009b).

Negative Regulator of endocytosis (EGFR, Transferrin receptor, EphA2). Suppression of endogenous SHIP2 in cancer cells (HeLa cervical cancer cells and MDA-231 breast cancer cells) decreases ligand-induced endocytosis of the EGFR and EphA2 (Prasad and Decker, 2005; Zhuang et al., 2007). SHIP2 function in the endocytosis of EGFR is characterized by a direct and constitutive association between SHIP2 and c-Cbl ubiquitin ligase and changes in EGFR-Cbl association. Whereas SHIP2 directly interacts with EphA2 via SAM-domain and this interaction may be important for EphA2 endocytosis (Zhuang et al., 2007). SHIP2 associates with intersectin 1, a major regulator of EGFR endocytosis, and recruits it to the plasma membrane in response to EGF treatment (Xie et al., 2008).

Regulator of Cell Cycle progression and apoptosis. Early studies indicated a positive association between SHIP2 expression and cell proliferation where EGF increases the SHIP2 mRNA expression in thyrocytes (Pesesse et al., 1997). In addition, SHIP2 protein expression correlates with the EGFR expression in proliferating neurospheres (Muraille et al., 2001). Exogenous overexpression (using adenovirus vectors) of wild-type SHIP2 inhibits cell cycle progression in U87-MG glioblastoma cells (Taylor et al., 2000) and K562 leukemia cells (Giuriato et al., 2002) and of a dominant-negative SHIP2 (phosphatase-defective) increases proliferation of pancreatic beta-cells (Grempler et al., 2007). Whereas retroviral-mediated expression of SHIP2 does not inhibit cell cycle progression of Myeloma cells (Choi et al., 2002). Furthermore, RNAi-mediated suppression of endogenous SHIP2 in MDA-231 cells inhibits cell proliferation with G1 accumulation and decreased S-phase and delays in vivo tumorigenesis (Prasad et al., 2008). Retroviral-mediated expression of a catalytically inactive SHIP2 inhibits PDGF-induced proliferation of 3T3-L1 preadipocytes (Artemenko et al., 2009). Thus, this aspect of SHIP2 function appears to be influenced greatly by the experimental approach and/or the cell types employed.

Negative regulator of immune cell function. SHIP2 inhibits Fcgamma Receptor IIa signaling including Akt activation and NF-kb-dependent gene trasncription (Pengal et al., 2003), downregulates Fcgamma Receptor-mediated phagocytosis (Ai et al., 2006) and decreases mast cell degranulation (Leung and Bolland, 2007; Saini et al., 2009).


SHIP2 is structurally related to SHIP1, another phosphoinositol 5-phosphatase expressed exclusively in hematopoietic tissues. SHIP1 is an important negative regulator of immune receptor and cytokine signaling. SHIP1 and SHIP2 show 64% identity in their inositol phosphatase domains and 54% identity in their SH2-domains. The C-terminus proline-rich region carries the least similarity (also the SAM-domain is present only in SHIP2 and not in SHIP1) and appears to be the key for functional divergence between these two enzymes. In addition to the human gene, SHIP2 gene has been cloned from mouse, rat, cattle, dog, monkey, chimpanzee and zebra fish genomes.



There is R1142C mutation within the Proline-rich region of SHIP2 in Goto-Kakizaki (GK rats; a model for type 2 diabetes) and spontaneously hypertensive (SH-) rats. This mutation slightly impairs insulin signaling in cell culture (Marion et al., 2002).


In humans, a deletion in the SHIP2 3 untranslated region (UTR) has been identified in type 2 diabetic patients. In cell culture, this deletion enhances SHIP2 promoter activity in reporter assays and SHIP2 over-expression. This deletion is reported to be significantly associated with the presence of type 2 diabetes (Marion et al., 2002).

Implicated in

SHIP2 is expressed at high levels in Bcr-Abl transformed K562 CML cells where it is highly tyrosine phosphorylated and constitutively associated with the adapter protein Shc in K562 leukemia cells (Wisniewski et al., 1999). Adenoviral-mediated exogenous overexpression of SHIP2 in K562 cells inhibits cell cycle progression (see Function - Cell cycle regulation above).
Entity name
Breast cancer
SHIP2 is overexpressed in many breast cancer cells when compared to non-transformed mammary epithelial cells (Prasad et al., 2008). Stable SHIP2 RNA interference in MDA-231 and MDA-468 breast cancer cells decreases cell proliferation (Prasad et al., 2008; Prasad, 2009b). SHIP2 suppression also causes delayed tumorigenesis in nude mouse mammary fatpad xenograft studies (Prasad et al., 2008). SHIP2 overexpression is reported in clinical specimens of human breast cancers [n=65 (Prasad et al., 2008); and n=285 (Prasad et al., 2008)]. In invasive breast cancers (n=145), SHIP2 expression is positively correlated with reduced disease-free survival and estrogen receptor-negative (ER-) and EGF receptor-positive (EGFR+) status (Prasad et al., 2008).
Entity name
Hepatocellular carcinoma
SHIP2 expression in the cancer cells is decreased as compared to the adjacent normal cells of the same cancer specimens (n = 20) (Sumie et al., 2007). Any possible association between the SHIP2 levels and glucose intolerance or the aggressiveness of the disease remains to be examined.
Entity name
Type 2 diabetes
Single nucleotide polymorphisms (SNPs) in the SHIP2 gene promoter and the 5 untranlated region correlates with the impaired fasting glycemia in Japanese population (Ishida et al., 2006). The haplotypes found more frequently in glucose intolerant people increase transcription from SHIP2 promoter in reporter gene assays.
Evidence from transgenic animal studies in mouse showed that SHIP2 function in liver is important for insulin-dependent glucose homeostasis (Fukui et al., 2005; Buettner et al., 2007; Grempler et al., 2007; Kagawa et al., 2008).
Metabolic syndrome. Single nucleotide polymorphisms (SNPs) and haplotypes of SHIP2 are significantly correlated with symptoms of the metabolic syndrome including hypertension in British and French people from type 2 Diabetes families (Kaisaki et al., 2004). This association was not found with essential hypertension (not linked to metabolic syndrome) (Marcano et al., 2007).
Obesity. Evidence from gene knockout studies in mouse showed that SHIP2 deletion caused resistance to high-fat diet induced obesity (Sleeman et al., 2005) although insulin signaling was only mildly enhanced. These studies raised the possibility that global inhibition of SHIP2 will be tolerated (not lethal) without significant side-effects.


Pubmed IDLast YearTitleAuthors
161793752006The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1.Ai J et al
188141812009Catalytically inactive SHIP2 inhibits proliferation by attenuating PDGF signaling in 3T3-L1 preadipocytes.Artemenko Y et al
172335892007The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors?Astle MV et al
176728242007The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2.Batty IH et al
146834602003SHIP2: an emerging target for the treatment of type 2 diabetes mellitus.Baumgartener JW et al
117150232001Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.Bodine SC et al
173273702007Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome.Buettner R et al
153160172004Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2.Chi Y et al
121496502002PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells.Choi Y et al
128471082003SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles.Déléris P et al
173712352007Metabolic switching of PI3K-dependent lipid signals.Downes CP et al
159642362005The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2.Dyson JM et al
126767852003SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton.Dyson JM et al
117394142001The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin.Dyson JM et al
159831952005Impact of the liver-specific expression of SHIP2 (SH2-containing inositol 5'-phosphatase 2) on insulin signaling and glucose metabolism in mice.Fukui K et al
128852972003SH2-containing inositol 5-phosphatases 1 and 2 in blood platelets: their interactions and roles in the control of phosphatidylinositol 3,4,5-trisphosphate levels.Giuriato S et al
175964042007Normalization of prandial blood glucose and improvement of glucose tolerance by liver-specific inhibition of SH2 domain containing inositol phosphatase 2 (SHIP2) in diabetic KKAy mice: SHIP2 inhibition causes insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis.Grempler R et al
96608331998Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein.Habib T et al
85300881995Cloning and characterization of a human cDNA (INPPL1) sharing homology with inositol polyphosphate phosphatases.Hejna JA et al
121451492002Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice.Hori H et al
171237772007Transcriptional profiling of C2C12 myotubes in response to SHIP2 depletion and insulin stimulation.Huard C et al
168044142006Association of SH-2 containing inositol 5'-phosphatase 2 gene polymorphisms and hyperglycemia.Ishida S et al
180397902008Impact of transgenic overexpression of SH2-containing inositol 5'-phosphatase 2 on glucose metabolism and insulin signaling in mice.Kagawa S et al
152202172004Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome.Kaisaki PJ et al
157356642005The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading.Koch A et al
105823341999SHIPs ahoy.Krystal G et al
165828772006Lipid phosphatases as drug discovery targets for type 2 diabetes.Lazar DF et al
175790262007The inositol 5'-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production.Leung WH et al
175579292007Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension.Marçano AC et al
120869272002The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man.Marion E et al
115302392001The SH2 domain-containing 5-phosphatase SHIP2 is expressed in the germinal layers of embryo and adult mouse brain: increased expression in N-CAM-deficient mice.Muraille E et al
126901042003SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling.Pengal RA et al
93678311997Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP.Pesesse X et al
98243121998The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate 5-phosphatase activity.Pesesse X et al
122352912002Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I.Prasad N et al
156682402005SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor.Prasad NK et al
190650642008High expression of obesity-linked phosphatase SHIP2 in invasive breast cancer correlates with reduced disease-free survival.Prasad NK et al
190824822009SHIP2 phosphoinositol phosphatase positively regulates EGFR-Akt pathway, CXCR4 expression, and cell migration in MDA-MB-231 breast cancer cells.Prasad NK et al
107169402000Structure, function, and biology of SHIP proteins.Rohrschneider LR et al
117150222001Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways.Rommel C et al
194776902009Cultured peripheral blood mast cells from chronic idiopathic urticaria patients spontaneously degranulate upon IgE sensitization: Relationship to expression of Syk and SHIP-2.Saini SS et al
116921742001SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes.Sasaoka T et al
168428572006Lipid phosphatases as a possible therapeutic target in cases of type 2 diabetes and obesity.Sasaoka T et al
156543252005Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.Sleeman MW et al
176717002007Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection.Sumie S et al
1095868220005' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells.Taylor V et al
112389002001Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity.Wada T et al
155571762004SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating factor (M-CSF) stimulation and regulates M-CSF-induced signaling.Wang Y et al
101944511999A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells.Wisniewski D et al
186920522008SHIP2 associates with intersectin and recruits it to the plasma membrane in response to EGF.Xie J et al
190334582008MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.Yu J et al
154940232004Analysis of insulin signalling by RNAi-based gene silencing.Zhou QL et al
171352402007Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation.Zhuang G et al

Other Information

Locus ID:

NCBI: 3636
MIM: 600829
HGNC: 6080
Ensembl: ENSG00000165458


dbSNP: 3636
ClinVar: 3636
TCGA: ENSG00000165458


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Inositol phosphate metabolismKEGGko00562
Phosphatidylinositol signaling systemKEGGko04070
B cell receptor signaling pathwayKEGGko04662
Insulin signaling pathwayKEGGko04910
Inositol phosphate metabolismKEGGhsa00562
Phosphatidylinositol signaling systemKEGGhsa04070
B cell receptor signaling pathwayKEGGhsa04662
Insulin signaling pathwayKEGGhsa04910
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Inositol phosphate metabolismREACTOMER-HSA-1483249
Synthesis of IP3 and IP4 in the cytosolREACTOMER-HSA-1855204
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
PI MetabolismREACTOMER-HSA-1483255
Synthesis of PIPs at the plasma membraneREACTOMER-HSA-1660499

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
190334582008MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.106
205302482010MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2.53
178932312008Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover.31
120869272002The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man.30
156682402005SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor.28
186604892008Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.26
201140252010Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation.24
204530002010A Large-scale genetic association study of esophageal adenocarcinoma risk.23
152202172004Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome.22
189913942008NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor.22


Nagendra K Prasad

INPPL1 (inositol polyphosphate phosphatase-like 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

Online version: