Abstract
Endocytic sorting of activated receptor tyrosine kinases (RTKs), alternating between recycling and degradative processes, controls signal duration, location and surface complement of RTKs. The microtubule (MT) plus‐end tracking proteins (+TIPs) play essential roles in various cellular activities including translocation of intracellular cargo. However, mechanisms through which RTKs recycle back to the plasma membrane following internalization in response to ligand remain poorly understood. We report that net outward‐directed movement of endocytic vesicles containing the hepatocyte growth factor (HGF) Met RTK, requires recruitment of the +TIP, CLIP‐170, as well as the association of CLIP‐170 to MT plus‐ends. In response to HGF, entry of Met into Rab4‐positive endosomes results in Golgi‐localized γ‐ear‐containing Arf‐binding protein 3 (GGA3) and CLIP‐170 recruitment to an activated Met RTK complex. We conclude that CLIP‐170 co‐ordinates the recycling and the transport of Met‐positive endocytic vesicles to plus‐ends of MTs towards the cell cortex, including the plasma membrane and the lamellipodia, thereby promoting cell migration.
Highlights
Receptor tyrosine kinases (RTKs) control many aspects of cell behavior, including proliferation, survival, differentiation and migration in response to their environment
To assess the impact of CLIP170 depletion and the expression of GFP-CLIP-170 CC domain of CLIP-115 (CC115) on HGFmediated MT dynamics, we examined the behavior of MTs in response to hepatocyte growth factor (HGF) and the epidermal growth factor (EGF) by live imaging in cells expressing EGFP-α-tubulin
We describe a molecular mechanism whereby the +TIP, CLIP-170, is required for recycling of Met RTK to the cell cortex and is linked to HGFdependent biological responses
Summary
Receptor tyrosine kinases (RTKs) control many aspects of cell behavior, including proliferation, survival, differentiation and migration in response to their environment. RTKs become catalytically active and tyrosine phosphorylated, enabling the recruitment of proteins to initiate downstream signaling cascades These processes are balanced by the simultaneous recruitment of endocytic proteins, which enhance RTK internalization, allowing for their removal from the cell surface and subsequent signal termination.[1] Receptor internalization is recognized as an important mechanism for regulating the signal transduction of functional receptors at the plasma membrane (PM).[1,2] a molecular understanding of the processes that modulate spatially restricted signaling of RTKs after internalization is key to our understanding of a biological response. These results link both endocytic and MT-based processes in Met RTKmediated biological outcomes
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