Centrosomal JAK2 in ciliated cells

The National Institute of General Medical Sciences awarded the University of Toledo $573,750 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to characterize centrosomal JAK2 localization in ciliated cells and define how it regulates ciliogenesis and downstream cellular functions. The research investigates JAK2, a non-receptor protein tyrosine kinase, as a novel component of centrosome-associated complexes and its role in controlling cilia formation, cilia-based signaling, cell-cycle progression, and cell migration in normal and disease states. The work addresses a knowledge gap in spatial regulation of JAK2 at the centrosome to establish fundamental mechanisms by which centrosomal JAK2 contributes to ciliopathies and cancer. Work is performed in Ottawa Hills, Ohio, with a period of performance extending from September 1, 2026, through August 31, 2029. The research is structured around two specific aims: determining whether centrosomal JAK2 regulates ciliogenesis and cilia-dependent cell functions, and characterizing centrosomal JAK2's role in the centrosome-associated complex through mechanisms informed by preliminary experimental data.

Abstract

JAK2 is an ubiquitously expressed non-receptor protein tyrosine kinases, activated by a variety of cytokines, growth factors, and gpcr ligands. JAK2 activity is linked to diverse cellular functions, including cell-cycle progression, apoptosis, proliferation, differentiation, survival, genomic stability, and chromatin organization. Consequently, JAK2 dysregulation contributes to multiple pathologies. However, a critical knowledge GAP remains in how JAK2 is spatially regulated, particularly at the centrosome, to control signaling in normal and disease states. The long-term of our research is to establish important insight into fundamental mechanisms by which JAK2, localized to the centrosome (cent-JAK2), works to contribute to ciliopathies and cancer. The rationale for the proposed research is that JAK2 is a novel component of a centrosome-associated complex and that this localization modulates both centrosomal functions and JAK2 kinase activity, thereby tuning cytokine-activated pathways. We have identified two regions within JAK2 that direct its centrosomal localization. The overall objective of this application is to characterize the cent-JAK2 complex in ciliated cells and define how IT regulates ciliogenesis and downstream cellular functions, including proliferation and migration. The central hypothesis is that JAK2, localized at the centrosome is a novel member of the centrosome-associated complex through which IT regulates ciliogenesis and other cell functions. Guided by strong preliminary data, we will pursue two specific aims. Specific aim 1 will determine whether cent-JAK2 regulates ciliogenesis, cilia-based signaling, and cilia-dependent cell functions (cell cycle and migration). Under the first aim, we will test the working hypothesis that cent-JAK2 controls cilia formation and cell-cycle progression and assess the impact of cent-JAK2 on ciliary GH-triggered signal transduction and cilia orientation. Specific aim 2 will test the hypothesis that cytokine-activated JAK2 promotes assembly of multiprotein complexes at the centrosome that regulate cilia resorption and cilia orientation. Under this aim, we will define cent-JAK2 interactions with the serine/threonine kinase PAK1 to control cilia resorption and with the actin-binding protein filamin a to regulate cilia orientation in migrating cells, and elucidate the underlying mechanisms. This proposal is conceptually innovative because this work reframes JAK2 as a spatially organized, centrosome-localized regulator of ciliary structure and signaling, expanding beyond canonical plasma- membrane paradigms. The proposed research is significant because elucidating cent-JAK2 signaling will reveal mechanisms that couple cytokine input to ciliary dynamics and cell behavior, providing new avenues to target human cancers and ciliopathies.