Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion

Abstract

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). We have previously shown that the Drosophila Alk RTK is crucial for visceral mesoderm development during early embryogenesis. Notably, observed Alk visceral mesoderm defects are highly reminiscent of the phenotype reported for the secreted molecule Jelly belly (Jeb). Here we show that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm, and that Jeb binding stimulates an Alk-driven, extracellular signal-regulated kinase-mediated signalling pathway, which results in the expression of the downstream gene duf (also known as kirre)--needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of Duf expression by the Drosophila Alk RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and jeb mutant animals.

What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

“…50 Consistent with hyperactivation of the Ras pathway, phosphorylated ERK (pErk, the activated form of the kinase) has been detected in tumour cells derived from NPM-ALK transgenic mice, 22,23 confirming data generated in Drosophila and cell lines. 41,44,[51][52][53] The stress-activated JNK MAP Kinase pathway is also active in the tumour tissues of NPM-ALK transgenic mice. 23 Whereas in some cellular contexts stress-induced JNK activation appears to mediate apoptosis, in tumour cells JNK can signal cell survival.…”

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

“…Interestingly, in Drosophila, the 560 amino-acid protein jelly belly (Jeb) was shown by mutation and phenotypic analysis to interact with the fly ALK homolog dALK (Englund et al, 2003;Lee et al, 2003) and to induce MAPK signaling. No known homolog of Jeb has yet been described for vertebrates and our recent searches did not reveal a Jeb-related vertebrate protein or gene in the databases of either National Center for Biotechnology Information or EMBL.…”

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

“…. [39][40][41] The observation that in chick, a distinct set of skeletal muscles of the limbs, together with motor neurons innervating these regions, are ALK-positive during embryo development, 31 suggests a possible role in neuromuscular synapse formation.…”

“…Both defects caused an abnormal development of the visceral mesoderm, due to a lack of visceral muscle founder cells. [39][40][41][42] DALK is also expressed within the nervous system of Drosophila at later developmental stages, 43 but its role in this tissue is only starting to be elucidated. A very elegant study from Palmer's group recently found complementary patterns of expression for DALK and its ligand jeb in the fly developing visual system.…”