SCOP/PHLPP and its functional role in the brain

Abstract

SCOP (suprachiasmatic nucleus (SCN) circadian oscillatory protein) was originally identified in 1999 in a differential display screen of the rat SCN for genes whose expression were regulated in a circadian manner (K. Shimizu, M. Okada, A. Takano and K. Nagai, FEBS Lett., 1999, 458, 363-369). The SCN is the principle pacemaker of the circadian clock, and expression of SCOP protein in the SCN was found to oscillate, increasing during the subjective night, even when animals were housed in constant darkness. SCOP interacts with and inhibits multiple proteins important for intracellular signaling, either by directly binding to K-Ras or by dephosphorylating p-Akt and p-PKC. Since the functions of K-Ras, Akt, and PKC are considerably divergent, SCOP may have several roles. We recently discovered that SCOP participates in the formation of long-term hippocampus-dependent memories, and other investigators have examined its role in cell proliferation and survival. In this review, we introduce SCOP from its molecular structure to its physiological functions, focusing mainly on its role in ERK1/2 activation and memory consolidation.

Fig. 1

The domain composition of SCOP. Positions of the PH, LRR, PP2C-like, Q-rich, and PDZ-binding domains in the mouse SCOP protein are indicated.

Fig. 2

Immunoblot analysis of SCOP protein distribution. Protein extracts were prepared from various tissues of adult male rats. Marked immunoreactivity was observed only in the brain (cerebrum and cerebellum) and testes. Immunoreactivity of the testes migrated slightly faster than the predicted 183 kDa SCOP protein.

Fig. 3

LRR sequence homology of SCOP, adenylyl cyclase, and SUR-8. Alignment of 18 SCOP LRRs and the consensus across SCOP, yeast adenylyl cyclase (AC), and human SUR-8 are shown. Residues conserved in the majority of LRRs are shaded in blue. Allowable substitutions for leucine residues are outlined in red.

Fig. 4

SCOP negatively regulates activation of K-Ras. Ras cycles between a GTP-bound active state and a GDP-bound inactive state via GTP hydrolysis and GDP–GTP exchange steps. Guanine nucleotide exchange factors (GEFs) interact, reduce the affinity of Ras for GDP, facilitating formation of the nucleotide-free form, to which GTP binds for its activation. GTPase activating proteins (GAPs) increase the intrinsic GTPase activity of Ras and thereby promote its inactivation. SCOP is unique in that it binds to the nucleotide-free form to inhibit formation of the GTP-bound active form.

Fig. 5

SCOP localization within the neuron. SCOP is expressed in the cytosol, on membranes, and in membrane rafts. SCOP colocalizes with and binds to K-Ras in membrane rafts. SCOP is also reported to have phosphatase activity in non-neuronal cells, which may have other functions in neurons. Inset: In the hippocampus, SCOP attenuates ERK1/2 activity by binding to the nucleotide-free form of K-Ras, thereby inhibiting the ERK signaling pathway. Calpain-mediated degradation of SCOP may contribute to activation of ERK1/2.