Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1(SHIP1) is an
enzyme with
phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5Dgene in humans.[5][6][7] SHIP1 is expressed predominantly by
hematopoietic cells[8] but also, for example, by
osteoblasts[9] and
endothelial cells.[10] This phosphatase is important for the regulation of cellular activation. Not only
catalytic but also
adaptor activities of this protein are involved in this process. Its movement from the
cytosol to the
cytoplasmic membrane, where predominantly performs its function, is mediated by
tyrosine phosphorylation of the intracellular chains of
cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different
pathologies.[11]
At the N-terminus of the protein,
SH2 domain is formed. This domain is important for the interaction of SHIP1 with the phosphorylated protein chains that SHIP1 binds. Highly conserved phosphatase domain is in central part of the protein. This catalytic domain is flanked on the N-terminal side by the
PH-like domain that binds
phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) and is overlapped on C-terminus with the
C2 domain that binds
phosphatidylinositol-3,4-bisphosphate (PI(4, 5)P2). The C-tail is not structured, but contains a
proline-rich region that forms the motif for binding
SH3 domain and also contains sequence containing
tyrosine 915 (Y915) and tyrosine 1022 (Y1022) (in human cell) that is typical for interaction with the
phosphotyrosine binding domain (PTB domain).
Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on
serine 440 (Ser440), this phosphorylation is mediated by
cAMP-dependent protein kinase A (PKA).[12] Second
allosteric regulation is mediated by binding PI(3,4)P2 to the C2 domain.[13] Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation.[14]
Function
At the plasma membrane, the protein
hydrolyzes the 5' phosphate from
phosphatidylinositol (3,4,5)-trisphosphate and
inositol-1,3,4,5-tetrakisphosphate, thereby influence the binding of many proteins to the cytoplasmic membrane thus affecting multiple
signaling pathways. To access the substrate which is located on the cytoplasmic membrane, SHIP1 move from cytosol to the plasma membrane. This movement is mediated by binding its SH2 domain to the phosphorylated intracellular chains of cell surface receptors. Binding SHIP1 to phosphorylated
immunoreceptor tyrosine-based inhibition motifs (ITIM) of
FcγRIIB inhibits the activation of
B cells including Ca2+ influx.[15] SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling.[16][17] Overall, the protein functions as a negative regulator of cell proliferation and survival. Nevertheless, SHIP1 may also bind to partially phosphorylated
immunoreceptor tyrosine-based activation motifs (ITAM) of some cell surface receptors, for example
T cell receptor (TCR)[18] and
CD79a/b.[19] SHIP1 does not bind only to intracellular chains of cell surface receptor. Its SH2 domain may also interact with phosphorylated cytoplasmic proteins, such as
SHC1[20] and
DOK1.[21]
The regulation of signaling by SHIP1 is not dependent only on its catalytic activity. SHIP1 can also affect cell signaling pathways independently on its catalytic activity by serving as a bridge for other proteins thereby regulate
protein-protein interactions.
Poor regulation of the SHIP1 function leads to different pathologies. On the one hand, its increased activity is associated with
tumorogenesis. On the other hand, its low activity leads to
autoinflammatory diseases.[11] This knowledge is used in
drug development. In the case of autoinflammatory diseases, there is an attempt to increase SHIP1 catalytic activity by binding the small molecule to the C2 domain. This molekule should to act as
allosteric activator. Currently, some molecules are under development and tested as potential
anti-inflammatorydrug.
AQX-1125 (Rosiptor) and
AQX-MN100 are both in
clinical trials.[32][33][13]
^Manno B, Oellerich T, Schnyder T, Corso J, Lösing M, Neumann K, Urlaub H, Batista FD, Engelke M, Wienands J (November 2016). "The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner". European Journal of Immunology. 46 (11): 2520–2530.
doi:
10.1002/eji.201646431.
hdl:11858/00-001M-0000-002C-799C-E.
PMID27550373.
S2CID5676779.
^D'Ambrosio D, Hippen KL, Cambier JC (August 1996). "Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor". European Journal of Immunology (in French). 26 (8): 1960–5.
doi:
10.1002/eji.1830260842.
PMID8765045.
S2CID13612988.
^AdisInsight.
"AQX-1125". Springer. Archived from the original on 15 July 2016. Retrieved 20 July 2016.{{
cite web}}: CS1 maint: bot: original URL status unknown (
link)
Drayer AL, Pesesse X, De Smedt F, Woscholski R, Parker P, Erneux C (August 1996). "Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase". Biochemical and Biophysical Research Communications. 225 (1): 243–9.
doi:
10.1006/bbrc.1996.1161.
PMID8769125.
Zhang S, Broxmeyer HE (January 1999). "p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells". Biochemical and Biophysical Research Communications. 254 (2): 440–5.
doi:
10.1006/bbrc.1998.9959.
PMID9918857.
Bone H, Welham MJ (March 2000). "Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains". Cellular Signalling. 12 (3): 183–94.
doi:
10.1016/S0898-6568(99)00088-1.
PMID10704825.
Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD (May 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling. 12 (5): 317–26.
doi:
10.1016/S0898-6568(00)00073-5.
PMID10822173.
External links
Overview of all the structural information available in the
PDB for
UniProt: Q92835 (Human Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the
PDBe-KB.
Overview of all the structural information available in the
PDB for
UniProt: Q9ES52 (Mouse Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the
PDBe-KB.
Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1(SHIP1) is an
enzyme with
phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5Dgene in humans.[5][6][7] SHIP1 is expressed predominantly by
hematopoietic cells[8] but also, for example, by
osteoblasts[9] and
endothelial cells.[10] This phosphatase is important for the regulation of cellular activation. Not only
catalytic but also
adaptor activities of this protein are involved in this process. Its movement from the
cytosol to the
cytoplasmic membrane, where predominantly performs its function, is mediated by
tyrosine phosphorylation of the intracellular chains of
cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different
pathologies.[11]
At the N-terminus of the protein,
SH2 domain is formed. This domain is important for the interaction of SHIP1 with the phosphorylated protein chains that SHIP1 binds. Highly conserved phosphatase domain is in central part of the protein. This catalytic domain is flanked on the N-terminal side by the
PH-like domain that binds
phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) and is overlapped on C-terminus with the
C2 domain that binds
phosphatidylinositol-3,4-bisphosphate (PI(4, 5)P2). The C-tail is not structured, but contains a
proline-rich region that forms the motif for binding
SH3 domain and also contains sequence containing
tyrosine 915 (Y915) and tyrosine 1022 (Y1022) (in human cell) that is typical for interaction with the
phosphotyrosine binding domain (PTB domain).
Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on
serine 440 (Ser440), this phosphorylation is mediated by
cAMP-dependent protein kinase A (PKA).[12] Second
allosteric regulation is mediated by binding PI(3,4)P2 to the C2 domain.[13] Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation.[14]
Function
At the plasma membrane, the protein
hydrolyzes the 5' phosphate from
phosphatidylinositol (3,4,5)-trisphosphate and
inositol-1,3,4,5-tetrakisphosphate, thereby influence the binding of many proteins to the cytoplasmic membrane thus affecting multiple
signaling pathways. To access the substrate which is located on the cytoplasmic membrane, SHIP1 move from cytosol to the plasma membrane. This movement is mediated by binding its SH2 domain to the phosphorylated intracellular chains of cell surface receptors. Binding SHIP1 to phosphorylated
immunoreceptor tyrosine-based inhibition motifs (ITIM) of
FcγRIIB inhibits the activation of
B cells including Ca2+ influx.[15] SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling.[16][17] Overall, the protein functions as a negative regulator of cell proliferation and survival. Nevertheless, SHIP1 may also bind to partially phosphorylated
immunoreceptor tyrosine-based activation motifs (ITAM) of some cell surface receptors, for example
T cell receptor (TCR)[18] and
CD79a/b.[19] SHIP1 does not bind only to intracellular chains of cell surface receptor. Its SH2 domain may also interact with phosphorylated cytoplasmic proteins, such as
SHC1[20] and
DOK1.[21]
The regulation of signaling by SHIP1 is not dependent only on its catalytic activity. SHIP1 can also affect cell signaling pathways independently on its catalytic activity by serving as a bridge for other proteins thereby regulate
protein-protein interactions.
Poor regulation of the SHIP1 function leads to different pathologies. On the one hand, its increased activity is associated with
tumorogenesis. On the other hand, its low activity leads to
autoinflammatory diseases.[11] This knowledge is used in
drug development. In the case of autoinflammatory diseases, there is an attempt to increase SHIP1 catalytic activity by binding the small molecule to the C2 domain. This molekule should to act as
allosteric activator. Currently, some molecules are under development and tested as potential
anti-inflammatorydrug.
AQX-1125 (Rosiptor) and
AQX-MN100 are both in
clinical trials.[32][33][13]
^Manno B, Oellerich T, Schnyder T, Corso J, Lösing M, Neumann K, Urlaub H, Batista FD, Engelke M, Wienands J (November 2016). "The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner". European Journal of Immunology. 46 (11): 2520–2530.
doi:
10.1002/eji.201646431.
hdl:11858/00-001M-0000-002C-799C-E.
PMID27550373.
S2CID5676779.
^D'Ambrosio D, Hippen KL, Cambier JC (August 1996). "Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor". European Journal of Immunology (in French). 26 (8): 1960–5.
doi:
10.1002/eji.1830260842.
PMID8765045.
S2CID13612988.
^AdisInsight.
"AQX-1125". Springer. Archived from the original on 15 July 2016. Retrieved 20 July 2016.{{
cite web}}: CS1 maint: bot: original URL status unknown (
link)
Drayer AL, Pesesse X, De Smedt F, Woscholski R, Parker P, Erneux C (August 1996). "Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase". Biochemical and Biophysical Research Communications. 225 (1): 243–9.
doi:
10.1006/bbrc.1996.1161.
PMID8769125.
Zhang S, Broxmeyer HE (January 1999). "p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells". Biochemical and Biophysical Research Communications. 254 (2): 440–5.
doi:
10.1006/bbrc.1998.9959.
PMID9918857.
Bone H, Welham MJ (March 2000). "Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains". Cellular Signalling. 12 (3): 183–94.
doi:
10.1016/S0898-6568(99)00088-1.
PMID10704825.
Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD (May 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling. 12 (5): 317–26.
doi:
10.1016/S0898-6568(00)00073-5.
PMID10822173.
External links
Overview of all the structural information available in the
PDB for
UniProt: Q92835 (Human Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the
PDBe-KB.
Overview of all the structural information available in the
PDB for
UniProt: Q9ES52 (Mouse Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the
PDBe-KB.