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

Author:

Akbulut Simge1,Reddi Alagarsamy L.2,Aggarwal Priya2,Ambardekar Charuta2,Canciani Barbara2,Kim Marianne K.H.2,Hix Laura2,Vilimas Tomas2,Mason Jacqueline3,Basson M. Albert4,Lovatt Matthew5,Powell Jonathan6,Collins Samuel6,Quatela Steven7,Phillips Mark7,Licht Jonathan D.12

Affiliation:

1. *Division of Hematology and Oncology, Mount Sinai School of Medicine, New York, NY 10029;

2. Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

3. The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada;

4. Department of Craniofacial Development, King's College London, London SE1 9RT, United Kingdom;

5. National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom;

6. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21218-2696; and

7. New York University Cancer Institute, New York, NY 10016-6497

Abstract

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 IP3at 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.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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