Regulation of the Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase
Open accessAbstract
Many agents that activate hematopoietic cells use phos pha tidyl ino si tol 3,4,5-trisphosphate (PtdIns 3,4,5-P(3)) to initiate signaling cascades. The SH2 domain-containing inositol 5' phosphatase, SHIP1, regulates hematopoietic cell function by opposing the action of phos pha tidyl ino si tol 3-kinase and reducing the levels of PtdIns 3,4,5-P(3). Activation of the cyclic AMP-de pend ent protein kinase (PKA) also opposes many of the pro-inflammatory responses of hematopoietic cells. We tested to see whether the activity of SHIP1 was regulated via phos pho ryl a tion with PKA. We prepared pure recombinant SHIP1 from HEK-293 cells and found it can be rapidly phos pho ryl a ted by PKA to a stoichiometry of 0.6 mol of PO(4)/mol of SHIP1. In (32)P-labeled HEK-293 cells transfected with SHIP1, stimulation with Sp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt hydrate (Sp-cAMPS) or activation of the beta-adrenergic receptor increased the phos pho ryl a tion state of SHIP1. Inhibition of protein phosphatase activity with okadaic acid also increased the phos pho ryl a tion of SHIP1. Phosphorylation of SHIP1 in vitro or in cells by PKA increased the 5' phosphatase activity of SHIP1 by 2-3-fold. Elevation of Ca(2+) in DT40 cells in response to B cell receptor cross-linking, an indicator of PtdIns 3,4,5-P(3) levels, was markedly blunted by pretreatment with Sp-cAMPS. This effect was absent in SHIP(-/-) DT40 cells showing that the effect of Sp-cAMPS in DT40 cells is SHIP1-de pend ent. Sp-cAMPS also blunted the ability of the B cell receptor to increase the phos pho ryl a tion of Akt in DT40 and A20 cells. Overall, activation of G protein-coupled receptors that raise cyclic AMP cause SHIP1 to be phosphorylated and stimulate its inositol phosphatase activity. These results outline a novel mechanism of SHIP1 regulation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SHIP1 can be phosphorylated at Ser440 within the 5' phosphatase domain by PKA to increase phosphatase activity.
“SHIP1 can be phosphorylated at Ser440 within the 5’ phosphatase domain by PKA to increase the phosphatase activity.”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [110]
The Results (page unavailable) show that PKA phosphorylates SHIP1 and increases its catalytic activity about twofold. Our copy does not identify Ser440 as the phosphorylation site or place that site within the 5′-phosphatase domain, so those specifics are not supported. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
Adenosine receptors: therapeutic aspects for inflammatory and immune diseases
Haskó, G., Linden, J. M., Cronstein, B. N., & Pacher, P. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2638 · Cited by 1,224 · see citing works
Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation
Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., & Wymann, M. P. (2000) · Science · doi:10.1126/science.287.5455.1049 · Cited by 1,209 · see citing works
PI3K in lymphocyte development, differentiation and activation
Okkenhaug, K., & Vanhaesebroeck, B. (2003) · Nature reviews. Immunology · doi:10.1038/nri1056 · Cited by 812 · see citing works
Molecular Approach to Adenosine Receptors: Receptor-Mediated Mechanisms of Tissue Protection
Linden, J. M. (2001) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.41.1.775 · Cited by 681 · see citing works
Deletion of SHIP or SHP-1 Reveals Two Distinct Pathways for Inhibitory Signaling
Ono, M., Okada, H., Bolland, S. M., Yanagi, S., Kurosaki, T., & Ravetch, J. V. (1997) · Cell · doi:10.1016/s0092-8674(00)80337-2 · Cited by 488 · see citing works
The role of PI3K in immune cells
Koyasu, S. (2003) · Nature Immunology · doi:10.1038/ni0403-313 · Cited by 486 · see citing works
Drug discovery approaches targeting the PI3K/Akt pathway in cancer
Garcı́a-Echeverrı́a, C., & Sellers, W. R. (2008) · Oncogene · doi:10.1038/onc.2008.246 · Cited by 474 · see citing works
PTEN and Myotubularin: Novel Phosphoinositide Phosphatases
Maehama, T., Taylor, G. S., & Dixon, J. E. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.247 · Cited by 462 · see citing works
SHIP Modulates Immune Receptor Responses by Regulating Membrane Association of Btk
Bolland, S. M., Pearse, R. N., Kurosaki, T., & Ravetch, J. V. (1998) · Immunity · doi:10.1016/s1074-7613(00)80555-5 · Cited by 384 · see citing works
The role of PTEN signaling perturbations in cancer and in targeted therapy
Keniry, M. E., & Parsons, R. E. (2008) · Oncogene · doi:10.1038/onc.2008.248 · Cited by 358 · see citing works
P hosphoinositide 3-K inase : Diverse Roles in Immune Cell Activation
Deane, J. A., & Fruman, D. A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104721 · Cited by 347 · see citing works
PTEN: from pathology to biology
Sulis, M. L. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00175-2 · Cited by 342 · see citing works
LPS-Induced Upregulation of SHIP Is Essential for Endotoxin Tolerance
Sly, L. M., Rauh, M. J., Kalesnikoff, J., Song, C., & Krystal, G. (2004) · Immunity · doi:10.1016/j.immuni.2004.07.010 · Cited by 308 · see citing works
Understanding PTEN regulation: PIP2, polarity and protein stability
Leslie, N. R., Batty, I. H., Maccario, H., Davidson, L., & Downes, C. P. (2008) · Oncogene · doi:10.1038/onc.2008.243 · Cited by 221 · see citing works
Zhuo, S., Clemens, J. C., Hakes, D. J., Barford, D., & Dixon, J. E. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)46769-x · Cited by 174 · see citing works
Ong, C. J., Ming‐Lum, A., Nodwell, M., Ghanipour, A., Yang, L., Williams, D. E., Kim, J., Demirjian, L., Qasimi, P., Rüschmann, J., et al. (2007) · Blood · doi:10.1182/blood-2007-03-079699 · Cited by 161 · see citing works
Sullivan, G. W., Rieger, J. M., Scheld, W. M., Macdonald, T. L., & Linden, J. M. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703893 · Cited by 158 · see citing works
Murphree, L. J., Sullivan, G. W., Marshall, M. A., & Linden, J. M. (2005) · Biochemical Journal · doi:10.1042/bj20050888 · Cited by 138 · see citing works
Okadaic Acid: The Archetypal Serine / Threonine Protein Phosphatase Inhibitor
Dounay, A. B., & Forsyth, C. J. (2002) · Current Medicinal Chemistry · doi:10.2174/0929867023368791 · Cited by 136 · see citing works
Gold, M. R., Scheid, M. P., Santos, L., Dang-Lawson, M., Roth, R. A., Matsuuchi, L., Duronio, V., & Krebs, D. L. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.4.1894 · Cited by 133 · see citing works
Lipid phosphatases in the immune system
Krystal, G. (2000) · Seminars in Immunology · doi:10.1006/smim.2000.0222 · Cited by 131 · see citing works
A-kinase-interacting protein localizes protein kinase A in the nucleus
Sastri, M., Barraclough, D. M., Carmichael, P. T., & Taylor, S. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408608102 · Cited by 127 · see citing works
Brauweiler, A. M., Tamir, I., Porto, J. D., Benschop, R. J., Helgason, C. D., Humphries, R. K., Freed, J. H., & Cambier, J. C. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.9.1545 · Cited by 123 · see citing works
Lamkin, T. D., Walk, S. F., Liu, L., Damen, J. E., Krystal, G., & Ravichandran, K. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.16.10396 · Cited by 118 · see citing works
Self-citationMcColl, S. R., St‐Onge, M., Dussault, A., Laflamme, C., Bouchard, L., Boulanger, J., & Pouliot, M. (2005) · The FASEB Journal · doi:10.1096/fj.05-4804fje · Cited by 117 · see citing works
A Sensitive Assay for Phosphoinositide Phosphatases
Maehama, T., Taylor, G. S., Slama, J. T., & Dixon, J. E. (2000) · Analytical Biochemistry · doi:10.1006/abio.2000.4497 · Cited by 116 · see citing works
Sly, L. M., Rauh, M. J., Kalesnikoff, J., Büchse, T., & Krystal, G. (2003) · Experimental Hematology · doi:10.1016/j.exphem.2003.09.011 · Cited by 105 · see citing works
Phee, H., Jacob, A., & Coggeshall, K. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001093200 · Cited by 99 · see citing works
Post-translational regulation of PTEN
Wang, X., & Jiang, X. (2008) · Oncogene · doi:10.1038/onc.2008.242 · Cited by 98 · see citing works
Giuriato, S., Payrastre, B., Drayer, A. L., Plantavid, M. M., Woscholski, R., Parker, P. J., Erneux, C., & Chap, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.43.26857 · Cited by 93 · see citing works
Regulation of interleukin-12 production byG-protein-coupled receptors
Braun, M., & Kelsall, B. L. (2001) · Microbes and Infection · doi:10.1016/s1286-4579(00)01357-5 · Cited by 77 · see citing works
Role of the inositol phosphatase SHIP in B cell receptor-induced Ca2+ oscillatory response.
Okada, H., Bolland, S. M., Hashimoto, A. S., Kurosaki, M., Kabuyama, Y., Iino, M., Ravetch, J. V., & Kurosaki, T. (1998) · PubMed · Cited by 73 · see citing works
Bléro, D., Smedt, F. D., Pesesse, X., Paternotte, N., Moreau, C., Payrastre, B., & Erneux, C. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.4639 · Cited by 71 · see citing works
The role of SHIP in macrophages
Sly, L. M. (2007) · Frontiers in bioscience · doi:10.2741/2276 · Cited by 66 · see citing works
Okada, H., Bolland, S. M., Hashimoto, A. S., Kurosaki, M., Kabuyama, Y., Iino, M., Ravetch, J. V., & Kurosaki, T. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.10.5129 · Cited by 66 · see citing works
Aman, M. J., Walk, S. F., March, M., Su, H.-P., Carver, D. J., & Ravichandran, K. S. (2000) · Molecular and Cellular Biology · doi:10.1128/.20.10.3576-3589.2000 · Cited by 61 · see citing works
Self-citationMayeenuddin, L. H., & Garrison, J. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506035200 · Cited by 57 · see citing works
Self-citationFcγRIIB1/SHIP-mediated Inhibitory Signaling in B Cells Involves Lipid Rafts
Aman, M. J., Tosello‐Trampont, A., & Ravichandran, K. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104069200 · Cited by 56 · see citing works
Self-citationBatty, I. H., KAAY, J. V. D., Gray, A., Telfer, J. F., Dixon, M. J., & Downes, C. P. (2007) · Biochemical Journal · doi:10.1042/bj20070558 · Cited by 41 · see citing works
Mature macrophage cell lines exhibit variable responses to LPS
Barbour, S. E., Wong, C., Rabah, D., Kapur, A., & Carter, A. D. (1998) · Molecular Immunology · doi:10.1016/s0161-5890(98)00070-4 · Cited by 36 · see citing works
Sun, W., Moore, J. N., Hurley, D. J., Vandenplas, M. L., Linden, J. M., Cao, Z., & Murray, T. F. (2007) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2007.08.011 · Cited by 32 · see citing works
Horn, S., Meyer, J., Heukeshoven, J., Fehse, B., Schulze, C., Li, S., Frey, J., Poll, S. N., Stocking, C., & Jücker, M. (2001) · Leukemia · doi:10.1038/sj.leu.2401990 · Cited by 24 · see citing works
Regulation of Phospholipase C‐γ2 Networks in B Lymphocytes
Hikida, M., & Kurosaki, T. (2005) · Advances in immunology · doi:10.1016/s0065-2776(05)88003-4 · Cited by 19 · see citing works
Review: G-protein-coupled Receptors on Eosinophils
Giembycz, M. A., Lynch, O. T., de Souza, P. M., & Lindsay, M. A. (2000) · Pulmonary Pharmacology & Therapeutics · doi:10.1006/pupt.2000.0250 · Cited by 13 · see citing works
Artemenko, Y., Gagnon, A., Ibrahim, S. M., & Sorisky, A. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.20965 · Cited by 11 · see citing works
March, M., Lucas, D. M., Aman, M. J., & Ravichandran, K. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003714200 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Sastri, M., Barraclough, D. M., Carmichael, P. T., and Taylor, S. S. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 349 -354
Cited by
Sorted by citations
Inhibitor and activator: dual functions for SHIP in immunity and cancer
Kerr, W. G. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05869.x · Cited by 111 · see citing works
Pauls, S. D., & Marshall, A. J. (2017) · European Journal of Immunology · doi:10.1002/eji.201646795 · Cited by 118 · see citing works
Terzioglu, G., & Young-Pearse, T. L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00674-9 · Cited by 95 · see citing works
Pauls, S. D., Lafarge, S. T., Landego, I., Zhang, T., & Marshall, A. J. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00224 · Cited by 76 · see citing works
Role of SHIP1 in cancer and mucosal inflammation
Fernandes, S. R. M., Iyer, S., & Kerr, W. G. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12038 · Cited by 41 · see citing works
Cooney, J. D., Lin, A., Jiang, D., Wang, L., Suhasini, A. N., Myers, J., Qiu, Z., Wölfler, A., Sill, H., & Aguiar, R. C. T. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2218 · Cited by 25 · see citing works
Zhang, J., Ravichandran, K. S., & Garrison, J. C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.128827 · Cited by 25 · see citing works
Self-citationSHIP negatively regulates type II immune responses in mast cells and macrophages
Dobranowski, P., & Sly, L. M. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mir0817-340r · Cited by 19 · see citing works
Strategy for Leukemia Treatment Targeting SHP-1,2 and SHIP
Hao, F., Wang, C., Sholy, C., Cao, M., & Kang, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.730400 · Cited by 18 · see citing works
SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy
Yeoh, W. J., & Krebs, P. (2023) · European Journal of Immunology · doi:10.1002/eji.202350446 · Cited by 14 · see citing works
Discovery and evaluation of novel SHIP-1 inhibitors
Miao, J., Lin, J., Dong, J., Amarasinghe, O., Mason, E. R., Chu, S., Qu, Z., Cullers, C. C., Putt, K. S., & Zhang, Z. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117965 · Cited by 7 · see citing works
Regulation of FcεRI Signaling by Lipid Phosphatases
Kuhny, M., Zorn, C. N., & Huber, M. (2014) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-07911-0_6 · Cited by 3 · see citing works
A new paradigm in phosphoinositide signaling? (Comment on DOI 10.1002/bies.201100195)
So, E., & Mui, A. (2012) · BioEssays · doi:10.1002/bies.201200091 · Cited by 1 · see citing works
ERK/MAPK Pathway Regulation of GABA-A Receptor Function.
Dohi, A. (2009) · Digital Commons @ UNT Health Science Center
SHIP and Tumour-Associated Macrophages
Ho, V. W., Hamilton, M. J., Kuroda, E., Rüschmann, J., Antignano, F., Lam, V., & Krystal, G. (2011) · Springer eBooks · doi:10.1007/978-1-4614-0662-4_10
The Role of Aberrantly Spliced SHIP1 in T-Cell Acute Lymphoblastic Leukemia
Williams, R. T. (2013) · eScholarship (California Digital Library)
Dysregulation of System Xc- and Its Impact on Cocaine Seeking
Madayag, A. (2012) · e-Publications@Marquette (Marquette University)
BindingDB Entry 50023001: Discovery and evaluation of novel SHIP-1 inhibitors.
BindingDB (2026) · UC San Diego · doi:10.7270/q22z1bds
- Authors
- Zhang, J., Walk, S. F., Ravichandran, K. S., & Garrison, J. C.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Garrison, James C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 284
- Issue
- 30
- Pages
- 20070-20078
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2740433
- OpenAlex
- W2017164427
- Cited by
- 18
- References
- 47
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2021: 1 · 2018: 1 · 2017: 2 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM076236)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK199520, P30DK067629)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- SHIP1, protein kinase A, protein phosphorylation, phosphatidylinositol 3-kinase, hematopoietic cells, beta-adrenergic receptors, B cell receptor signaling, Akt phosphorylation, G protein-coupled receptors, okadaic acid, calcium signaling, phosphatase activity, anti-inflammatory signaling
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Cyclic AMP, Animals, B-Lymphocytes, Cell Line, Humans, Kidney, Phosphoric Monoester Hydrolases, Phosphorylation, Receptors, Adrenergic, beta, Recombinant Proteins, Thionucleotides, Gene Expression, Lymphoma, B-Cell, Cyclic AMP-Dependent Protein Kinases, src Homology Domains, Cell Line, Tumor, Mice, Protein Phosphatase 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
