The role of ALK in vivo
Our lab has a strong focus working with Drosophila melanogaster as a powerful genetic model as well as with cultured, tumour-derived human cells. Recently, we have extended our studies to transgenic mice and xenograft models. Therefore, we employ molecular biology, histology and modern microscopy techniques. In 2014 we moved from Umeå to the Sahlgrenska Academy at the University of Gothenburg where our lab is situated in the Institute of Biomedicine.
In our laboratory we are interested in intercellular signal transduction events mediated by the Anaplastic Lymphoma kinase (ALK) receptor. Our aim is to understand the importance and function of ALK signalling during development and disease. Over the last 15 years we have been mainly interested in the following questions:
•What are the activating ligands for the ALK receptor?
•How is ALK expression regulated?
•Which factors participate in ALK signalling?
•What are the cellular responses upon ALK signalling; what are the transcriptional targets?
The Drosophila Alk protein is expressed in the embryonic visceral musculature, where it has been well characterized. Loss of Alk, or its ligand Jelly Belly (Jeb), results in impaired specification of the visceral muscle founder cells, resulting in a failure of cell fusion, leading to late embryonic/early larval lethality.
Activation of Alk by Jelly belly (Jeb) leads to activation of a signaling pathway in the visceral mesoderm that directs specification of muscle founder cells. This is accompanied by a number of events, including regulation of the expression of dpp, org, hand and flamigo, as well as exclusion of the Lmd protein from the nucleus.
Ligands for human ALK have recently been identified as FAM150A and FAM150B, which bind to the extracellular domain of ALK and potently activate it.
Vertebrate ALK share similarities in the glycine-rich region in the membrane of the proximal portion of their extracellular domains, as well as within the kinase domain, with the related Leukocyte Tyrosine Kinase (LTK) RTK.
When analyzing different tissues from humans, ALK mRNA expression is found in a number of tissues including adult brain, small intestine, colon, prostate and testis. The neuronal expression of ALK suggests a function for the ALK this receptor in the developing nervous system.
Activation of Anaplastic Lymphoma Kinase (ALK) in cancer is commonly due to fusion of the ALK kinase domain with a dimerization partner that drives activation. However, ALK activation also occurs in the context of the full length receptor, e.g. as activating point mutations in neuroblastoma. In many additional tumor types ALK overexpression and activation has been described, and it is unclear whether this is dependent on activity of a ligand.