Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

Autor: Charuta Ambardekar, Simge Akbulut, Barbara Canciani, Steven E. Quatela, Priya Aggarwal, Mark Phillips, Alagarsamy Lakku Reddi, Tomas Vilimas, Jacqueline M. Mason, M. Albert Basson, Samuel L. Collins, Jonathan D. Licht, Jonathan D. Powell, Matthew Lovatt, Laura M. Hix, Marianne K.H. Kim
Rok vydání: 2010
Předmět:
Antigens
Differentiation
T-Lymphocyte
endocrine system
Transcription
Genetic
T-Lymphocytes
Intracellular Space
Receptors
Antigen
T-Cell
Inositol 1
4
5-Trisphosphate
Protein Serine-Threonine Kinases
Biology
Receptor tyrosine kinase
Diglycerides
Mice
03 medical and health sciences
0302 clinical medicine
Antigens
CD
Animals
Immunoprecipitation
Lectins
C-Type
Molecular Biology
Adaptor Proteins
Signal Transducing
030304 developmental biology
Calcium signaling
Diacylglycerol kinase
0303 health sciences
Phospholipase C
Phospholipase C gamma
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Signal transducing adaptor protein
Articles
Cell Biology
Phosphoproteins
Molecular biology
Signaling
Cell biology
Enzyme Activation
030220 oncology & carcinogenesis
SPRY2
NIH 3T3 Cells
ras Proteins
biology.protein
Phosphorylation
Calcium
Mitogen-Activated Protein Kinases
Biomarkers
Protein Binding
Proto-oncogene tyrosine-protein kinase Src
Zdroj: Molecular Biology of the Cell
ISSN: 1939-4586
1059-1524
DOI: 10.1091/mbc.e10-02-0123
Popis: PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors.
Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling; however, their exact mechanism of action remains incompletely understood. We identified phosphatidylinositol-specific phospholipase C (PLC)-γ as a partner of the Spry1 and Spry2 proteins. Spry–PLCγ interaction was dependent on the Src homology 2 domain of PLCγ and a conserved N-terminal tyrosine residue in Spry1 and Spry2. Overexpression of Spry1 and Spry2 was associated with decreased PLCγ phosphorylation and decreased PLCγ activity as measured by production of inositol (1,4,5)-triphosphate (IP3) and diacylglycerol, whereas cells deficient for Spry1 or Spry1, -2, and -4 showed increased production of IP3 at baseline and further increased in response to growth factor signals. Overexpression of Spry 1 or Spry2 or small-interfering RNA-mediated knockdown of PLCγ1 or PLCγ2 abrogated the activity of a calcium-dependent reporter gene, suggesting that Spry inhibited calcium-mediated signaling downstream of PLCγ. Furthermore, Spry overexpression in T-cells, which are highly dependent on PLCγ activity and calcium signaling, blocked T-cell receptor-mediated calcium release. Accordingly, cultured T-cells from Spry1 gene knockout mice showed increased proliferation in response to T-cell receptor stimulation. These data highlight an important action of Spry, which may allow these proteins to influence signaling through multiple receptors.
Databáze: OpenAIRE
Externí odkaz: