RAS-MPAK Pathway Signaling in Health and Disease

The p21ras (Ras) family of signal switch molecules is an essential component of proliferative responses to many extracellular stimuli including most hematopoietic growth factors and cytokines. Phosphorylation of tyrosine residues on activated cytokine/growth factor receptors triggers multiple signaling pathways including JAK/STAT, Ras and PI3K. Activated Ras proteins further activate downstream effectors such as RAF/MEK/ERK, PI3K and RalGDS. Point mutations of Ras proteins are commonly found in human cancers and are estimated to occur in about 30% of cancer cases. These mutations lock Ras in the constitutively active conformation. In addition to point mutations of RAS, other genetic lesions such as the BCR-ABL fusion, PTPN11 mutations, FLT3 internal tandem duplications, CBL mutations and NF1 inactivation all lead to hyperactive Ras signaling. Besides cancers, RAS and Ras-activating mutations have been found in RASopathies, such as Neurofibromatosis type 1 (NF1), Noonan Syndrome, Costello syndrome, and Cardiofaciocutaneous syndrome (CFC).RAS mutations are highly prevalent in hematologic malignancies including chronic and juvenile myelomonocytic leukemia (CMML and JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and multiple myeloma (MM). In contrast to epithelial cancers where KRAS mutations are highly prevalent, most mutations found in hematologic malignancies alter NRAS. Human genetic data and results from genetic mouse models support the idea that dereg...
Source: Blood - Category: Hematology Authors: Tags: A MAP(K) to Pediatric RASopathies Source Type: research