Activation of receptor tyrosine kinases (RTKs) by secreted growth factors regulates cell proliferation and cell fate

Activation of receptor tyrosine kinases (RTKs) by secreted growth factors regulates cell proliferation and cell fate determination in many different cellular and developmental contexts. Despite such widespread functions, RTK signalling involves a common cytoplasmic cascade including Ras, and the serine-threonine kinases Raf, MAPKK/MEK and MAPK. Thus, a central issue is how activation of the same cytoplasmic components elicits distinct responses depending on the cell context (Hill and Treisman, 1995; Simon, 2000). The nuclear response to the signal depends in many cases on the availability of different transcription factors for direct phosphorylation by the Ras/Raf pathway. In addition, RTK signalling can trigger mechanisms of either activation or repression of gene expression, adding an extra level of complexity to the final output. Thus, cell responses to RTK signalling are largely determined by the mechanisms and factors that mediate transcriptional regulation downstream of the RTK cascade. A well-established model of RTK signalling concerns the formation of veins in the Drosophila wing. The insect wings consist of a bilayer of epidermal cells closely apposed by their basal sides that secrete a thin and transparent cuticle. In Drosophila, wings display a stereotyped pattern of five longitudinal veins and two transverse crossveins. The veins are specialised epithelial cells present in both wing surfaces. During late differentiation, dorsal and ventral veins match accurately providing a hollow space for the passage of axons and trachea (García-Bellido and de Celis, 1992). Vein tissue specification occurs during larval and pupal stages within the wing imaginal discs, and involves a complex network of gene regulation. Central to this network is the Epidermal Growth Factor Receptor (EGFR) RTK (DíazBenjumea and Hafen, 1994), which, in Drosophila, functions in a wide spectrum of developmental processes such as oogenesis, patterning of embryonic structures such as the ventral epidermis and trachea, and specification of photoreceptor cells in the compound eye (Schweitzer and Shilo, 1997). In wing discs, activation of EGFR in rows of cells causes their determination as prospective wing veins. Consistent with this function, loss-of-function mutations in components of the EGFR pathway cause loss of veins, whereas gain-of-function alleles and/or overexpression of those components result in ectopic vein development (DíazBenjumea and Hafen, 1994). The role of EGFR signalling in vein patterning involves complex molecular interactions that (1) restrict its activity to appropriate cells, and (2) impose cell fate changes in response to signalling. Activation of EGFR in precise rows of cells 993 Development 129, 993-1002 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV7917