Cell cycle control and spatio-temporal regulation of ERK signaling by KSR1

KSR1 is a molecular scaffold for the Raf/MEK/ERK cascade and is required for the temporal and spatial regulation of the pathway. KSR1 is required for maximal ERK activation following growth factor stimulation and promotes distinct cellular fates such as cell growth, transformation, and senescence. In addition to its role in mitogenic signaling, KSR1 is emerging as an important regulator in the cellular response to DNA damage. Our data reveal that KSR1 is required for maximal ERK activation following UV, IR, and MMC-induced DNA damage. KSR1 is only required, however, for the re-initiation of the cell cycle following MMC-induced G2/M arrest. Interestingly, KSR1 was not required for the re-entry of the cell cycle following UV or IR. KSR1 may elicit diverse cellular fates in response to specific types of DNA damage. These data reveal a novel link between the Raf/MEK/ERK pathway and its involvement in the DNA damage response.Additionally, KSR1 functions to spatially regulate the MAPK pathway. KSR1 is required for ERK activation at caveolae. We hypothesize that KSR1 localizes to caveolae through its interaction with caveolin-1. Caveolin-1 negatively regulates the MAPK pathway by directly inhibiting MEK and ERK. It is possible that KSR1 inhibits the negative effects of caveolin-1 to promote ERK signaling from caveolae. Indeed we show that loss of KSR1 from caveolae delays ERK activation. Localization of KSR1 to caveolae or its potential interaction with caveolin-1 is required for ERK-mediated effects such as transformation and senescence. Furthermore we show that caveolin-1 also negatively regulates KSR1. Loss of caveolin-1 increases ERK activation and proliferation. Additionally, caveolin-1-deficient MEFs expressing ectopic KSR1 transform even in the absence of an activating oncogene. These data suggest a novel reciprocal relationship between KSR1 and caveolin-1 to mediate ERK signaling from caveolae. Understanding the molecular mechanisms by which KSR1 facilitates spatio-temporal regulation of ERK signals may provide insights into the role of KSR1 in mediating proliferation and transformation.