The c-Jun NH(2)-terminal kinases (JNKs) are an evolutionarily conserved sub-group of mitogen-activated protein (MAP) kinases. Recent studies have improved our understanding of the physiological function of the JNK pathway. Roles of novel molecules that participate in the JNK pathway have been defined and new insight into the role of JNK in survival signaling, cell death, cancer and diabetes has been achieved.

Both the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways can protect cells from apoptosis following withdrawal of survival factors. We have previously shown that the ERK1/2 pathway acts independently of PI3K to block expression of the BH3-only protein, Bim EL , and prevent serum withdrawal-induced cell death, although the precise mechanism by which ERK reduced Bim EL levels was unclear. By comparing Bim mRNA and Bim protein, expression we now show that the rapid expression of Bim EL following serum withdrawal cannot be accounted for simply by increases in mRNA following inhibition of PI3K. In cells maintained in serum Bim EL is a phosphoprotein. We show that activation of the ERK1/2 pathway is both necessary and sufficient to promote Bim EL phosphorylation and that this leads to a substantial increase in turnover of the Bim EL protein. ERK1/2-dependent degradation of Bim EL proceeds via the proteasome pathway because it is blocked by proteasome inhibitors and is defective at the restrictive temperature in cells with a temperaturesensitive mutation in the E1 component of the ubiquitinconjugating system. Finally, co-transfection of Bim EL and FLAG-ubiquitin causes the accumulation of polyubiquitinated forms of Bim, and this requires the ERK1/2 pathway. Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival.

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The c-Jun NH 2 -terminal kinase (JNK) group of mitogen-activated protein kinases is stimulated in response to a wide array of cellular stresses and proinflammatory cytokines. Mice lacking individual members of the Jnk family (Jnk1, Jnk2, and Jnk3) are viable and survive without overt structural abnormalities. Here we show that mice with a compound deficiency in Jnk expression can survive to birth, but fail to close the optic fissure (retinal coloboma). We demonstrate that JNK initiates a cytokine cascade of bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh) that induces the expression of the paired-like homeobox transcription factor Pax2 and closure of the optic fissure. Interestingly, the role of JNK to regulate BMP4 expression during optic fissure closure is conserved in Drosophila during dorsal closure, a related morphogenetic process that requires JNK-regulated expression of the BMP4 ortholog Decapentaplegic (Dpp).

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The murine JNK-interacting protein 3 (JIP3) protein (also known as JSAP1) is expressed exclusively in neurons and has been identified as a scaffold protein for the c-Jun NH 2-terminal kinase (JNK) signaling pathway and as an adapter protein for cargo transport by the microtubule motor protein kinesin. To investigate the physiological function of JIP3, we examined the effect of Jip3 gene disruption in mice. The Jip3 ؊/؊ mice were unable to breathe and died shortly after birth. Microscopic analysis demonstrated that Jip3 gene disruption causes severe defects in the morphogenesis of the telencephalon. Jip3 ؊/؊ mice lack the telencephalic commissure, a major connection between the left and right hemispheres of the brain. The central nervous system abnormalities of Jip3 ؊/؊ mice may be accounted for in part by a reduction in signal transduction by RhoA and its effector ROCK.

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