Inhibition of growth-factor-induced phosphorylation and activation of protein kinase B/Akt by atypical protein kinase C in breast cancer cells

M. Mao, X. Fang, Y. Lu, R. LaPushin, Jr Bast, Gordon Mills

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Abstract

The protein kinase B/Akt serine/threonine kinase, located downstream of phosphoinositide 3-kinase (PI-3K), is a major regulator of cellular survival and proliferation. Atypical protein kinase C (aPKC) family members are activated by PI-3K and also contribute to cell proliferation, suggesting that Akt and aPKC might interact to activate signalling through the PI-3K cascade. Here we demonstrate that blocking PKC activity in MDA-MB-468 breast cancer cells increased the phosphorylation and activity of Akt. Functional PI-3K was required for the PKC inhibitors to increase Akt phosphorylation and activation, potentially owing to the activation of specific PKC isoforms by PI-3K. The concentration dependence of the action of the PKC inhibitors implicates aPKC in the inhibition of Akt phosphorylation and activity. In support of a role for aPKC in the regulation of Akt, Akt and PKCζ or PKCλ/ι were readily co-precipitated from the BT-549 breast cancer cell line. Furthermore, the overexpression of PKCζ inhibited growth-factor-induced increases in Akt phosphorylation and activity. Thus PKCζ associates physically with Akt and decreases Akt phosphorylation and enzyme activity. The effects of PKC on Akt were transmitted through the PI-3K cascade as indicated by changes in p70 s6 kinase (p70δ6κ) phosphorylation. Thus PKCζ, and potentially other PKC isoenzymes, regulate growth-factor-mediated Akt phosphorylation and activation, which is consistent with a generalized role for PKCζ in limiting growth factor signalling through the PI-3K/Akt pathway.

Original languageEnglish (US)
Pages (from-to)475-482
Number of pages8
JournalBiochemical Journal
Volume352
Issue number2
DOIs
Publication statusPublished - Dec 1 2000
Externally publishedYes

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Keywords

  • Atypical PKC
  • Epidermal growth factor
  • p70
  • Phosphoinositide 3-kinase
  • PKC inhibitor

ASJC Scopus subject areas

  • Biochemistry

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