Acute renal failure secondary to tubular epithelial ischemic injury is a major cause of patient morbidity. Renal tubular epithelial cell injury results in dramatic cellular phenotypic changes including alterations in morphology and induction of genetic programs thought to be critical for regulating the cell's response to injury. Depending on the type or extent of injury, proximal tubular epithelial cells either sustain sublethal injury and recover, or die and are replaced. Investigating the proximal signaling pathways that regulate these responses should provide better understanding of the complex nature of these responses to injury. Stress activating protein kinases or c-Jun N-terminal kinases (JNK) are rapidly activated by multiple cellular stresses including renal ischemia/reperfusion injury and are implicated in regulating processes as diverse as cell proliferation, apoptosis, and development. We have identified, cloned from embryonic kidney, and initially characterized the protein kinase called DLK. DLK is a MAP kinase kinase kinase of the mixed lineage kinase family (MLK) that may be activated by cellular injury and is capable of activating JNK. In the kidney, DLK is uniquely expressed in the proximal tubular epithelium. Given these observations, we hypothesize that DLK represents a proximal component of a signaling pathway that participates in modulating the response to proximal tubular epithelial injury. In part, MLK-dependent JNK signaling might affect the tubular injury response by regulating Pax2 phosphorylation and activation. Critical for renal epithelial morphogenesis, the transcription factor Pax2 is re-expressed in proximal tubular epithelium following injury and may direct post-injury tubular regeneration. New data suggests that Pax2 transcriptional activity is regulated by JNK-mediated phosphorylation potentially via an MLK-dependent JNK pathway.This proposal seeks primarily to investigate the fundamental biochemistry and regulation of DLK within its JNK signaling complex or module. By using a combination of biochemical approaches and by characterizing a newly prepared DLK null mouse, this project will begin to investigate the role of DLK-dependent signaling in the kidney.
| Nihalani, D; Meyer, D; Pajni, S et al. (2001) Mixed lineage kinase-dependent JNK activation is governed by interactions of scaffold protein JIP with MAPK module components. EMBO J 20:3447-58 |
| Nihalani, D; Merritt, S; Holzman, L B (2000) Identification of structural and functional domains in mixed lineage kinase dual leucine zipper-bearing kinase required for complex formation and stress-activated protein kinase activation. J Biol Chem 275:7273-9 |
