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Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis.

Publication ,  Journal Article
Naga Prasad, SV; Jayatilleke, A; Madamanchi, A; Rockman, HA
Published in: Nat Cell Biol
August 2005

Phosphoinositide 3-kinase (PI(3)K) is a unique enzyme characterized by both lipid and protein kinase activities. Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. Notably, knocking down endogenous tropomyosin expression using siRNAs that target different regions if tropomyosin resulted in complete inhibition of betaAR endocytosis, showing that non-muscle tropomyosin is essential for agonist-mediated receptor internalization. These studies demonstrate a previously unknown role for the protein phosphorylation activity of PI(3)K in betaAR internalization and identify non-muscle tropomyosin as a cellular substrate for protein kinase activity of PI(3)K.

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Published In

Nat Cell Biol

DOI

ISSN

1465-7392

Publication Date

August 2005

Volume

7

Issue

8

Start / End Page

785 / 796

Location

England

Related Subject Headings

  • beta-Arrestins
  • beta-Adrenergic Receptor Kinases
  • Wortmannin
  • Tropomyosin
  • Transferrin
  • Transfection
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Serine
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta
 

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Naga Prasad, S. V., Jayatilleke, A., Madamanchi, A., & Rockman, H. A. (2005). Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol, 7(8), 785–796. https://doi.org/10.1038/ncb1278
Naga Prasad, Sathyamangla V., Arundathi Jayatilleke, Aasakiran Madamanchi, and Howard A. Rockman. “Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis.Nat Cell Biol 7, no. 8 (August 2005): 785–96. https://doi.org/10.1038/ncb1278.
Naga Prasad SV, Jayatilleke A, Madamanchi A, Rockman HA. Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005 Aug;7(8):785–96.
Naga Prasad, Sathyamangla V., et al. “Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis.Nat Cell Biol, vol. 7, no. 8, Aug. 2005, pp. 785–96. Pubmed, doi:10.1038/ncb1278.
Naga Prasad SV, Jayatilleke A, Madamanchi A, Rockman HA. Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005 Aug;7(8):785–796.

Published In

Nat Cell Biol

DOI

ISSN

1465-7392

Publication Date

August 2005

Volume

7

Issue

8

Start / End Page

785 / 796

Location

England

Related Subject Headings

  • beta-Arrestins
  • beta-Adrenergic Receptor Kinases
  • Wortmannin
  • Tropomyosin
  • Transferrin
  • Transfection
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Serine
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta