Integrated regulation of motor-driven organelle transport by scaffolding proteins

Abstract

Intracellular trafficking pathways, including endocytosis, autophagy and secretion, rely on directed organelle transport driven by the opposing microtubule motor proteins kinesin and dynein. Precise spatial and temporal targeting of vesicles and organelles requires the integrated regulation of these opposing motors, which are often bound simultaneously to the same cargo. Recent progress demonstrates that organelle-associated scaffolding proteins, including Milton/TRAKs, JIP1, JIP3, huntingtin, and Hook1, interact with molecular motors to coordinate activity and sustain unidirectional transport. Scaffolding proteins also bind to upstream regulatory proteins including kinases and GTPases to modulate transport in the cell. This integration of regulatory control with motor activity allows for cargo-specific changes in the transport or targeting of organelles in response to cues from the complex cellular environment.

Megakaryocytic Maturation in Response to Shear Flow Is Mediated by the Activator Protein 1 (AP-1) Transcription Factor via Mitogen-activated Protein Kinase (MAPK) Mechanotransduction

“…JIP1 and JIP3 interact with Kinesin-1 and Dynactin and are involved in intracellular transport of signaling endosomes, autophagosomes, and mitochondria (61). In MKs, Dynactin is responsible for sliding PPT microtubules, whereas Kinesin carries organelles and granules throughout the PPTs shaft (68).…”

Intracellular cargo transport by kinesin-3 motors

“…the number of motors of each type loaded to a cargo molecule and the force that each motor can produce determine the net movement of the cargo [123,124]. Potential linkers to facilitate cooperation of dynein and kinesin 3 include Hook and Bicaudal, cargo adapter proteins that have been identified to interact with both dynein and kinesin 3 tail domains [41,69,125,126]. Interestingly, the presence of BICD2 increases the force generation and processivity of dynein/dynactin [127,128], demonstrating that these cargo adapter proteins regulate motor activity and could act as switches to control transport directionality within a complex containing two opposing motors.…”

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

“…The dynein/dynactin protein complex drives retrograde transport, moving damaged proteins for degradation, as well as critical signaling molecules such as neurotrophins, to the cell body (3). Dynein is a pleiotropic cellular motor, whose function in numerous cellular pathways may be regulated by specific interactions with different binding partners (4,5). In addition to its canonical role as a motor protein, dynein has been shown to have an anchoring role as well.…”