The long-term goal of ARO52785 is to understand the diversity of functions of the I-BAR family of cytoskeletal regulators through the study of the founding member Missing-in- Metastasis (MIM/MTSS1) in homeostasis and neoplasia. Work from ARO52785 demonstrates that MIM acts by blocking local actin polymerization through evolutionary conserved inhibitory interactions with the actin regulators Src kinase, atypical Protein Kinase C ?/? (Prkci), and cortactin (CTTN). Elimination of MIM, and either Src or CTTN, results in a restoration of normal function, highlighting the mutually antagonistic signaling. MIM's subcellular location and cell-type specific expression determines the site of actin regulation and the key processes it affects. I-BAR containing MIM accumulates at the plasma membrane to facilitate directional migration, while MIM isoforms with altered I-BAR domains localize to the basal body at the base of the sensory organelle, the primary cilium, to regulate Sonic Hedgehog (Shh) signaling during basal cell carcinoma (BCC) growth. MIM mutant mice created through ARO52785 funding also develop a profound progressive ataxia and early death due to the degeneration of cerebellar Purkinje neurons, although how MIM functions in this context remains unstudied. Our working hypothesis is that MIM promotes proper cell migration, morphogenic, and survival signaling by locally inhibiting Src and Prkci cytoskeletal kinases. ARO52785, now in its 6th year, will focus on gaps in our understanding of how this I-BAR protein contributes to ciliogenesis, neurodegeneration, and carcinogenesis in order to identify new therapeutic leads. We will: 1) Elucidate the mechanism of centrosomal MIM-dependent ciliogenesis by identifying the subcellular localization signals for MIM and determining how MIM and Prkci functionally interact with Src/CTTN;2) Dissect the role for MIM in progressive ataxia by elucidating the cellular basis of the MIM mutant phenotype and determining the role for Src/CTTN in ataxia progression;3) Elucidate the divergent roles for MIM in epithelial carcinogenesis by determining the role for MIM in BCC induction in vivo and investigating the role for MIM in inducing invasive breast cancer behavior in vivo. Completion of this work will provide clinically relevant and mechanistic insights into the importance of actin cytoskeletal regulation and provide clinical scenarios where MIM-regulated kinase inhibition may have therapeutic efficacy.
The long-term goal of ARO52785, now in its 6th year, is to understand the diversity of functions of Missing-in-Metastasis (MIM/MTSS1), the founding member of the I-BAR family of cytoskeletal regulators, in homeostasis and neoplasia. MIM promotes proper cell migration, ciliogenesis, and neuronal survival by blocking local actin polymerization through evolutionary conserved inhibitory interactions with Src kinase, atypical Protein Kinase C ?/?, and cortactin. ARO52785 will build upon mechanistic principles learned in the last funding period and focus on clinically-relevant gaps in our understanding of how MIM contributes to ciliogenesis, neurodegeneration, and carcinogenesis.
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