Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5؊/؊ mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.Cyclin-dependent kinase 5 (Cdk5) 1 is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1). Cdk5 kinase activity requires association with its neuronspecific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2-4). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6). Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7-11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system. Cdk5 has been implicated in both cell survival and programmed cell death in neuronal and nonneuronal systems (14,15). Cells induced to apoptosis by exogenous signals such as staurosporin display increased Cdk5 activity (16,17). Recently, Cdk5 in association with p25, a truncated form of p35, has been thought to be deregulated to produce hyperphosphorylated tau protein and to disrupt the neuronal cytoskeleton, and it may be involved in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral secrosis, Parkinson's disease, and Niemann-Pick disease (18 -23). On the other hand, Cdk5 may also be involved in neuronal survival. Cdk5 knockout mice exhibit a unique phenotype with perinatal mortality, associated with extensively disrupted cerebral cortical layering due to abnormal neuronal migration, absence of cerebella foliation, and degeneration of neurons...

The ERBB3 receptor in cancer and cancer gene therapy

“…247 In OVCAR3 cells, EGF led to activation of all four ERBB family members, but in the cell line OAW42, lacking ERBB3, EGF did not activate ERBB4 and NRG activated ERBB4 only after long exposure. These results indicate, for ovarian cancer cells, a central role for ERBB3 in activation of ERBB4, and suggest that ERBB3 itself is activated by a path other than the other ERBB receptors, either its own very weak kinase activity, or by recruitment of some other kinase known to increase its activation, such as PTK6 125 or c-SRC. 126 Another intriguing observation was the presence of truncated ERBB3 transcripts of 1.6, 1.7, 2.1 and 2.3 kb in ovarian carcinoma cells lines.…”

“…121,122 It may be that other pathways could also be involved: erlotinib-sensitive lung carcinoma cells expressed higher levels of the SRC-like kinase BRK; BRK is known to phosphorylate ERBB3 and promote PI3 kinase AKT signaling in mammary cells. 125 In addition, ERBB3 can be targeted independently of EGFR and ERBB2, as recently shown for the marine-derived anti-tumor agent kahalalide F. 428 In short, ERBB3 not only participates in the sensitivity of the majority of lung cancers that respond to EGFR tyrosine kinase inhibitors, but also in other malignancy-associated signaling paths. These multiple facets increase its attractiveness as a molecular target for therapy in this type of cancer.…”

“…149 PTK6-Protein tyrosine kinase 6 (PTK6, BRK), when highly expressed in mammary epithelial cells, resulted in enhanced phosphorylation of ERBB3 and downstream activation of AKT. 125 Its SH2 domain bound only at pY1276 (Table 3) and did not have affinity for the other ERBB proteins.…”

Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2

“…19 Cdk5 knockout mice show inhibition of the PI3K/Akt pathway in neurons. 12 Cdk5 phosphorylates the neuregulin receptor ErbB2/3 and thus is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. 12 An earlier study indicated that Akt phosphorylates Bad, a Bcl-2 family member, for cell survival.…”

“…12 Cdk5 phosphorylates the neuregulin receptor ErbB2/3 and thus is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. 12 An earlier study indicated that Akt phosphorylates Bad, a Bcl-2 family member, for cell survival. 36 In this study, we have shown that BDNF-induced Cdk5 kinase activity upregulated Bcl-2 during the neuronal differentiation.…”