Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

Abstract

The pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) differentially attenuates Akt, PKC, and ERK1/2 signaling, thereby controlling the duration and amplitude of responses evoked by these kinases. PHLPP1 is expressed in the mammalian central clock, the suprachiasmatic nucleus, where it oscillates in a circadian fashion. To explore the role of PHLPP1 in vivo, we have generated mice with a targeted deletion of the PHLPP1 gene. Here we show that PHLPP1-null mice, although displaying normal circadian rhythmicity, have a drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing a large phase shift after light resetting. Our findings reveal that PHLPP1 exerts a previously unappreciated role in circadian control, governing the consolidation of circadian periodicity after resetting.Per | period | after-effect | suprachiasmatic nucleus | phase shift E ssential properties of the mammalian circadian clock are a self-sustained oscillation under constant conditions and the dynamic resetting induced by light. These properties of the clock are necessary for humans and other mammals where they control cyclical activities as disparate as the sleep/wake cycle, metabolism, and cardiac function (1-3). The fine tuning of the endogenous clock by exogenous cues (zeitgebers) can be especially apparent when one travels across time zones or is transferred to a night shift working schedule (4). Circadian rhythms in mammals are driven by the central pacemaker, which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus (5). Light administration during the subjective night activates neurons of the retino-hypothalamic tract that target the SCN, and thereby resets behavioral rhythmicity. If mice are exposed to a light stimulus in the early night the clock delays, whereas it advances if light is given at late night (5, 6), underscoring the adaptability of the clock to changing lighting environment. Although there have been remarkable advances in deciphering the molecular organization of the circadian clock (1, 7), understanding of the molecular pathways involved in light-induced clock resetting is still incomplete (5).PHLPP1 and PHLPP2 (pleckstrin homology domain leucinerich repeats protein phosphatases 1 and 2) are Ser/Thr protein phosphatases that have been implicated in the regulation of various signaling pathways. These phosphatases negatively regulate Akt and protein kinase C (PKC) by direct dephosphorylation (8-10). In addition, a splice variant isoform of PHLPP1 (PHLPP1β, also known as suprachiasmatic nucleus circadian oscillatory protein, SCOP, see ref. 11) has been implicated in cognitive processes and its degradation appears to be required for long-term memory formation (12). PHLPP1 is thought to be involved in long-term memory formation by inhibiting ERK1/2 via direct binding to and inhibition of K-Ras, a small GTPase operating upstream of ERK1/2 (13). Interestingly, PHLPP1 (SCOP) is expressed in a circadian manner in the SCN, peaking in the sub...

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

“…Based on our findings it would be expected that knockout mice with targeted disruption of the PHLPP1 gene should develop a similar disorder. Such mice have recently been generated 50 and should provide a more definite answer whether loss of PHLPP1 expression contributes to the development and/or progression of CLL.…”

PHLPP-Mediated Dephosphorylation of S6K1 Inhibits Protein Translation and Cell Growth

“…) mice were kindly provided by A. Newton (19). The wild-type (WT) and PHLPP1 Ϫ/Ϫ mice used for breeding were littermates in a B6/129 mixed background.…”

Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation

“…Ϫ/Ϫ (20) and wild type (WT) littermates were maintained in an accredited facility with 12-hour light/dark cycles and supplied water and food (PicoLab Rodent Diet 20, LabDiet) ad libitum. All animal research was conducted according to National Institutes of Health and the Institute of Laboratory Animal Resources, National Research Council guidelines.…”

“…A number of phosphatases, including PH-domain leucine-rich repeat protein phosphatases (Phlpp) 2 1/2, dampen Akt activity to promote apoptosis and inhibit cell proliferation (17)(18)(19). Genetic deletion of Phlpp1 (also known as Phlpp, Scop, Plekhe1) slightly reduced snout-to-tail body lengths, but the effects of Phlpp1 on chondrocytes or growth plate structure were not studied (20).…”