Calreticulin and Jak2 as Chaperones for MPL: Insights into MPN Pathogenesis
Technical Report,01 Sep 2015,31 Aug 2016
University of New Mexico Albuquerque United States
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Calreticulin CALR is known to be a major player in the ER quality control of glycosylated proteins. Remarkably, this ubiquitously expressed housekeeping gene is mutated in 30 of patients with essential thrombocythemia ET and primary myelofibrosis PMF, two of the 8 major myeloproliferative neoplasms MPNs as classified by the WHO. One of the biggest challenges is to understand how Jak2,MPL and CALR mutant proteins can lead to very similar signaling events and phenotypes in these MPNs. We hypothesize that ET and PMF phenotypes result from abnormal signaling and aberrant intracellular trafficking events in cells bearing mutations in JAK2, MPL or CALR. In this project, we will acquire a deeper understanding of the interplay between these three gene products. We will compare and contrast intracellular routing for wild type and mutated proteins, identify their potential intersections, and determine the cellular locations from which signals are propagated. Our work seeks a broader understanding of the pathogenesis of the MPNs and set the stage for development of targeted therapeutic solutions.
- Genetic Engineering and Molecular Biology