Microtubules (MTs) are dynamic biopolymers, which serve as major trafficking highways in cells. MT-dependent transport is critical for physiology of all cell types, and disturbance of MT networks underlies many human diseases, from neurodegeneration to cancer. My laboratory studies global mechanisms whereby MT networks are built to perfectly attribute to specific cellular functions. To a large extent, MT network organization is defined by the sites from where new MTs initiate growth: the MT-organizing centers (MTOCs). MT architecture is also influenced by local stabilization/disassembly and sliding of existing MTs. Furthermore, affinity of individual MTs to molecular motors can be selectively modulated to provide fine-tuning of intracellular transport. While many mechanisms tailor MT organization to specific cell functions, the MT network can also respond dynamically according to signaling inputs and the physiological context. Molecular and spatial regulation of the MT network and functional specialization of MTs therein are not well understood. My research program?s long-term goals will be hugely facilitated by the MIRA, and include defining: how interphase MT networks are built and regulated; specific mechanisms tailoring MT geometry to specific cellular needs; molecular and cell biological mechanisms modulating MT network rebuilding during differentiation and different physiological inputs; how MT networks with different geometries act in concert, yet switch functional loads under changing signaling conditions; and, the methods whereby MTs collaborate with other cellular systems to build intracellular space. Toward these global and interactive goals, we have published numerous central discoveries in MT architecture organization (characterizing Golgi-derived MT networks (GDMTs); the allosteric regulation of MT plus-end binding complex by CLASP proteins; and, metabolic regulation of MT network for proper insulin secretion from beta cells), and MT function in cytoplasmic architecture (Golgi assembly and integrity; c-Src transport; and dynamics of invasive actin protrusions, the podosomes). In the next five years, I will extend the mechanistic and functional insight in three broad directions of my program?s extant NIGMS-supported research. (I) Regarding the Golgi complex as an alternative MTOC, we will determine what mechanisms underlie the spatial pattern of GDMT nucleation, how polarized GDMT arrays are organized, and how MTOC functions of the Golgi are tuned by calcium signaling and differentiation cues. (II) Regarding the roles of MT-binding proteins in MT network architecture, we will determine how paralogs of MT regulator CLASP exert specific functions and uncover MT-dependent functions of the tumor suppressor RASSF1A. (III) Exploring how the MT network provides architecture and functional organization within the cytoplasm, we will dissect the interplay of post-translational modifications of tubulin and molecular motors that position the Golgi while transitioning between cell-cycle stages in motile cells.
Microtubule networks, which serve as intracellular highways, dramatically change their organization to precisely address current functional demands dictated by cell-cycle, signaling, or differentiation cell state. Such microtubule rearrangements require tight regulation of microtubule nucleation, polymerization, and positioning. The goal of Kaverina laboratory research is to establish mechanistic and functional connections from the initial physiological signals to biochemistry and biophysics of microtubule networks, and further to microtubule-dependent cellular architecture and function.!
