Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57 Kip2

Devin T. Worster, Tobias Schmelzle, Nicole L. Solimini, Eric S. Lightcap, Bjorn Millard, Gordon B. Mills, Joan S. Brugge, John Albeck

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Epithelial cells respond to growth factors including epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), and insulin. Using high-content immunofluorescence microscopy, we quantitated differences in signaling networks downstream of EGF, which stimulated proliferation of mammary epithelial cells, and insulin or IGF-1, which enhanced the proliferative response to EGF but did not stimulate proliferation independently. We found that the abundance of the cyclin-dependent kinase inhibitors p21 Cip1 and p57 Kip2 increased in response to IGF-1 or insulin but decreased in response to EGF. Depletion of p57 Kip2, but not p21 Cip1, rendered IGF-1 or insulin sufficient to induce cellular proliferation in the absence of EGF. Signaling through the PI3K (phosphatidylinositol 3-kinase)-Akt-mTOR (mammalian target of rapamycin) pathway was necessary and sufficient for the increase in p57 Kip2, whereas MEK [mitogen-activated or extracellular signal-regulated protein kinase (ERK) kinase]-ERK activity suppressed this increase, forming a regulatory circuit that limited proliferation in response to unaccompanied Akt activity. Knockdown of p57 Kip2 enhanced the proliferative phenotype induced by tumor-associated PI3K mutant variants and released mammary epithelial acini from growth arrest during morphogenesis in three-dimensional culture. These results provide a potential explanation for the context-dependent proliferative activities of insulin and IGF-1 and for the finding that the CDKN1C locus encoding p57 Kip2 is silenced in many breast cancers, which frequently show hyperactivation of the PI3K pathway. The status of p57 Kip2 may thus be an important factor to assess when considering targeted therapy against the ERK or PI3K pathways.

Original languageEnglish (US)
Article numberra19
JournalScience Signaling
Volume5
Issue number214
DOIs
StatePublished - Mar 6 2012
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Somatomedins
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Cell Cycle
Breast
Epithelial Cells
Cells
Insulin
Cyclin-Dependent Kinase Inhibitor p57
Cyclin-Dependent Kinase Inhibitor p21
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Sirolimus
Morphogenesis
Mitogens
Fluorescence Microscopy
Protein Kinases
Tumors
Microscopic examination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57 Kip2 . / Worster, Devin T.; Schmelzle, Tobias; Solimini, Nicole L.; Lightcap, Eric S.; Millard, Bjorn; Mills, Gordon B.; Brugge, Joan S.; Albeck, John.

In: Science Signaling, Vol. 5, No. 214, ra19, 06.03.2012.

Research output: Contribution to journalArticle

Worster, Devin T. ; Schmelzle, Tobias ; Solimini, Nicole L. ; Lightcap, Eric S. ; Millard, Bjorn ; Mills, Gordon B. ; Brugge, Joan S. ; Albeck, John. / Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57 Kip2 In: Science Signaling. 2012 ; Vol. 5, No. 214.
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