JNK, cytoskeletal regulator and stress response kinase? A Drosophila perspective Deborah C.I. Goberdhan and Clive Wilson * Summary c-Jun N-terminal kinases (JNKs) are intracellular stress-activated signalling mol- ecules, which are controlled by a highly evolutionarily conserved signalling cascade. In mammalian cells, JNKs are regulated by a wide variety of cellular stresses and growth factors and have been implicated in the regulation of remarkably diverse biological processes, such as cell shape changes, immune responses and apoptosis. How can such different stimuli activate the JNK path- way and what roles does JNK play in vivo? Molecular genetic analysis of the Drosophila JNK gene has started to provide answers to these questions, confirm- ing the role of this molecule in development and stress responses and suggesting a conserved function for JNK signalling in processes such as wound healing. Here, we review this work and discuss how future experiments in Drosophila should reveal the cell type-specific mechanisms by which JNKs perform their diverse functions. BioEssays 20:1009–1019, 1998.  1998 John Wiley & Sons, Inc. In all higher eukaryotic organisms, cell–cell interactions and cellular responses to the extracellular environment play a central role in regulating cell development, survival, and physiology. Biochemical studies, primarily in cultured mamma- lian cells, have led to the identification of numerous intracellu- lar signalling cascades mediating such events. These path- ways are controlled by a variety of extracellular stimuli and probably act in a combinatorial fashion to perform multiple functions. A range of experimental approaches in mammals and simpler genetic organisms, such as the fruit fly, Drosophila melanogaster, and the nematode worm, Caenorhabditis el- egans, have allowed the multiple biological functions of a few signalling pathways to be examined in the whole organism. For example, the MAPK called ERK, which is regulated by a cascade of upstream kinases and the monomeric G protein Ras, can be activated by membrane-bound receptors such as RTKs to control differentiation, proliferation, and cell survival (Fig. 1). (1,2) The different functional outcomes of ERK activa- tion are believed to be determined by cellular context. In other words, the response to ERK activation is dependent on the other signalling pathways and cell type-specific transcription factors that are active in the cell. In recent years, the MAPK family has been extended by the identification of novel MAPK subfamilies that are distinct from ERKs. (3,4) Of these, JNK (SAPK1) (5) and p38 (SAPK2) (3,6) have attracted the most attention (Fig. 1). Experiments in mammalian cell culture systems have shown that these two alternative MAPK classes are regulated by overlapping, Research School of Biosciences, University of Kent at Canterbury, Canterbury, UK. Funding agencies: Biotechnology and Biological Sciences Research Council; Wellcome Trust. *Correspondence to: Clive Wilson, Research School of Biosciences, University of Kent at Canterbury, Canterbury, CT2 7NJ, UK. E-mail: c.wilson@ukc.ac.uk Abbreviations: aop, anterior open (allelic to yan); AP-1, c-Jun/c- Foshereodimer; bsk, basket; CL-100, MAPK phosphatase; dpp, deca- pentaplegic; dsh, dishevelled; ERK, extracellular signal-regulated kinase; fz, frizzled; hep, hemipterous; GTPase, guanosine triphospha- tase; IL-1, interleukin-1; JNK, c-Jun N-terminal kinase; LPS, lipopoly- saccharide; MAP, mitogen-activated protein; MAPK, MAP kinase; p38, stress-activated MAPK of 38 kDa; p65 PAK , downstream effector of Rho family proteins; puc, puckered; put, punt; RTK, receptor tyrosine kinase; SAPK, stress-activated protein kinase; TGF-, transforming growth factor-; tkv, thick veins; TNFR1, tumour necrosis factor receptor 1; UV, ultraviolet. Review articles BioEssays 20:1009–1019,  1998 John Wiley & Sons, Inc. BioEssays 20.12 1009