Unraveling the Molecular Mechanisms of the MRAS-SHOC2-PP1C Complex

The SMP complex, composed of SHOC2, MRAS, and PP1C, plays a crucial role in regulating the RAS-MAPK signaling pathway by facilitating RAF dephosphorylation and activation. Despite its significance in oncogenic and developmental signaling, the molecular mechanisms governing SMP complex assembly and function remain poorly understood. This proposal aims to elucidate the structural and biochemical basis of SMP complex formation, develop novel chemical probes to selectively disrupt its function, and investigate the roles of MRAS and SHOC2 in SMP complex assembly. Using an integrative approach that combines structural biology, chemical biology, medicinal chemistry, computational simulations, biophysical approaches, and cellular assays, we will define the key molecular interactions driving SMP complex activity. Furthermore, our chemical probes will serve as powerful tools to dissect the functional consequences of SMP disruption and lay the foundation for therapeutic strategies targeting aberrant RAS signaling. Collectively, this work will advance our understanding of SMP-mediated signal regulation and uncover potential avenues for therapeutic intervention in RAS-/RAF-driven malignancies and RASopathies. Project Number: 1R15GM163260-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Zhihong Wang | Institution: ROWAN UNIVERSITY, GLASSBORO, NJ | Award Amount: $581,250 | Activity Code: R15 | Study Section: Macromolecular Structure and Function A Study Section[MSFA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11292124