Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIP-mediated inhibitory signals.
Tec family non-receptor tyrosine kinases have been implicated in signal transduction events initiated by cell surface receptors from a broad range of cell types, including an essential role in B-cell development. A unique feature of several Tec members among known tyrosine kinases is the presence of an N-terminal pleckstrin homology (PH) domain. We directly demonstrate that phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3) interacting with the PH domain acts as an upstream activation signal for Tec kinases, resulting in Tec kinase-dependent phospholipase Cgamma (PLCgamma) tyrosine phosphorylation and inositol trisphosphate production. In addition, we show that this pathway is blocked when an SH2-containing inositol phosphatase (SHIP)-dependent inhibitory receptor is engaged. Together, our results suggest a general mechanism whereby PtdIns-3,4,5-P3 regulates receptor-dependent calcium signals through the function of Tec kinases.
Scharenberg
A M
AM
Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
El-Hillal
O
O
Fruman
D A
DA
Beitz
L O
LO
Li
Z
Z
Lin
S
S
Gout
I
I
Cantley
L C
LC
Rawlings
D J
DJ
Kinet
J P
JP
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001798:Blood Proteins / Q000235:genetics; D002118:Calcium / Q000502:physiology*; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D007295:Inositol Phosphates / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017452:Receptors, IgG / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000077329:Agammaglobulinaemia Tyrosine Kinase; D001798:Blood Proteins; D002118:Calcium; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D010744:Phosphoric Monoester Hydrolases; D011505:Protein-Tyrosine Kinases; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D010738:Type C Phospholipases; D014443:Tyrosine; C060974:phosphatidylinositol 3,4,5-triphosphate; C039077:platelet protein P47; C089848:Tec protein-tyrosine kinase; C080813:emt protein-tyrosine kinase; C098706:INPPL1 protein, human