Signal transduction in podocytes—spotlight on receptor tyrosine kinases

The mammalian kidney filtration barrier is a complex multicellular, multicomponent structure that maintains homeostasis by regulating electrolytes, acid–base balance, and blood pressure (via maintenance of salt and water balance). To perform these multiple functions, podocytes—an important component of the filtration apparatus—must process a series of intercellular signals. Integrating these signals with diverse cellular responses enables a coordinated response to various conditions. Although mature podocytes are terminally differentiated and cannot proliferate, they are able to respond to growth factors. It is possible that the initial response of podocytes to growth factors is beneficial and protective, and might include the induction of hypertrophic cell growth. However, extended and/or uncontrolled growth factor signalling might be maladaptive and could result in the induction of apoptosis and podocyte loss. Growth factors signal via the activation of receptor tyrosine kinases (RTKs) on their target cells and around a quarter of the 58 RTK family members that are encoded in the human genome have been identified in podocytes. Pharmacological inhibitors of many RTKs exist and are currently used in experimental and clinical cancer therapy. The identification of pathological RTK-mediated signal transduction pathways in podocytes could provide a starting point for the development of novel therapies for glomerular disorders

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-I studies regarding efficacy and potential toxicity of these compounds have already been reported