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Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38alpha mitogen-activated protein kinase via Sprouty2 downregulation.

ABSTRACT: Contact inhibition is a fundamental process in multicellular organisms aimed at inhibiting proliferation at high cellular densities through poorly characterized intracellular signals, despite availability of growth factors. We have previously identified the protein kinase p38alpha as a novel regulator of contact inhibition, as p38alpha is activated upon cell-cell contacts and p38alpha-deficient cells are impaired in both confluence-induced proliferation arrest and p27(Kip1) accumulation. Here, we establish that p27(Kip1) plays a key role downstream of p38alpha to arrest proliferation at high cellular densities. Surprisingly, p38alpha does not directly regulate p27(Kip1) expression levels but leads indirectly to confluent upregulation of p27(Kip1) and cell cycle arrest via the inhibition of mitogenic signals originating from the epidermal growth factor receptor (EGFR). Hence, confluent activation of p38alpha uncouples cell proliferation from mitogenic stimulation by inducing EGFR degradation through downregulation of the EGFR-stabilizing protein Sprouty2 (Spry2). Accordingly, confluent p38alpha-deficient cells fail to downregulate Spry2, providing them in turn with sustained EGFR signaling that facilitates cell overgrowth and oncogenic transformation. Our results provide novel mechanistic insight into the role of p38alpha as a sensor of cell density, which induces confluent cell cycle arrest via the Spry2-EGFR-p27(Kip1) network.

SUBMITTER: Swat A

PROVIDER: S-EPMC2698726 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38alpha mitogen-activated protein kinase via Sprouty2 downregulation.

Swat Aneta A Dolado Ignacio I Rojas Jose Maria JM Nebreda Angel R AR

Molecular and cellular biology 20090413 12

Contact inhibition is a fundamental process in multicellular organisms aimed at inhibiting proliferation at high cellular densities through poorly characterized intracellular signals, despite availability of growth factors. We have previously identified the protein kinase p38alpha as a novel regulator of contact inhibition, as p38alpha is activated upon cell-cell contacts and p38alpha-deficient cells are impaired in both confluence-induced proliferation arrest and p27(Kip1) accumulation. Here, w ...[more]

PMID: 19364817

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Project description:BackgroundThe mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway plays an important role in papillary and anaplastic thyroid cancer (PTC and ATC) due to activating mutations in BRAF, RAS, or rearrangements in RET/PTC1. The objective of this study was to thoroughly test whether the BRAF V600E mutation predicts response to mitogen-activated protein kinase kinase 1/2 (MKK1/2) inhibition, as shown in other tumor types, using an authenticated panel of thyroid cancer cell lines.MethodsPTC and ATC cells harboring distinct mutations in the MAPK pathway were treated with two different inhibitors selective for MKK1/2 (CI-1040 or U0126). The consequences of MKK1/2 inhibition on cell growth, survival, invasion, and MAPK signaling was determined.ResultsInhibition of MKK1/2 using CI-1040 or U0126 differentially inhibits the growth of a panel of PTC and ATC cell lines in two-dimensional culture, with those harboring the BRAF V600E mutation (SW1736) or BRAF-V600E/PI3K-E542K mutations (K1) being the most sensitive, the RET/PTC1 rearrangement (TPC1) and BRAF V600E mutant (BCPAP), intermediate, and the HRAS-G13R mutant (C643), the least sensitive. Growth of these cells is more sensitive to MKK1/2 inhibition when grown in 2% versus 10% serum. Baseline levels of phospho-ERK1/2 were similar in all of the cell lines, and inhibition phospho-ERK1/2 did not predict sensitivity to MKK1/2 inhibition. When cells are grown in three-dimensional culture, MKK1/2 inhibition of growth correlates with mutational status (BRAF > RET/PTC1 > RAS). Finally, PTC and ATC invasiveness is differentially inhibited by CI-1040, which is independent of tumor type or mutation present.ConclusionsDifferent mutations in the MAPK pathway play distinct roles in the growth and invasion of thyroid cancer cells. These results indicate that MKK1/2 inhibitors have the potential to inhibit thyroid cancer growth and invasion, but that responses differ based on mutation status and growth conditions.

Dataset Information

Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38alpha mitogen-activated protein kinase via Sprouty2 downregulation.

Publications

Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38alpha mitogen-activated protein kinase via Sprouty2 downregulation.

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