Identifying regulatory mechanisms of ROS1 signaling

This proposal aims to investigate the activation process of an unusual receptor tyrosine kinase (RTK) called ROS1. ROS1 plays important roles in various aspects of development and disease, including fertility, heart disease, and cancer. Unlike other RTK families, ROS1 receptors have a unique structure and the largest extracellular region (ECR) with predicted domains not found in any other RTK. However, the structure and regulation of ROS1 are still not well understood. This lack of understanding is partly due to the absence of a cell- based system to study its function and limited accessibility to structural and biophysical analysis due to its large ECR. We have overcome these obstacles and now plan to reveal the molecular mechanisms regulating ROS1 activation. Our goals for the next 10 years are to: 1) Gain a comprehensive understanding of how ROS1 receptors sense and transmit signals from their extracellular environment, 2) Investigate how receptor mutations and changes in the cellular matrix affect ROS1 signaling in disease, and 3) Explore whether the unique structural and regulatory elements of ROS1 could serve as novel targets for therapeutic interventions. Our research will involve studying the biochemical and structural aspects of ligand-receptor complexes to uncover how ligand binding leads to ROS1 activation in the signaling complex. By doing so, we aim to provide crucial insights into the signaling process of this distinct receptor family that deviates from the conventional RTK paradigm. This understanding will be essential for the development of effective inhibitors that target ROS1 specifically, as well as for devising clinical strategies to address ROS1-related diseases and their associated mutations. Project Number: 1R01GM153789-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Daryl Klein | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $1,409,649 | Activity Code: R01 | Study Section: Macromolecular Structure and Function C Study Section[MSFC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11226419