Kif5bEdit
KIF5B (kinesin family member 5B) is a motor protein that forms part of the kinesin-1 family, a group of molecular machines responsible for moving cargoes along microtubules inside cells. In humans, KIF5B is one of the major heavy chain components that power anterograde transport—from the cell body toward distal processes such as axons and dendrites in neurons, as well as in other polarized cell types. By partnering with kinesin light chains and diverse cargo adaptors, KIF5B helps move mitochondria, lysosomes, synaptic vesicle precursors, mRNAs, and other organelles to where they are needed. In the broader context of cell biology, KIF5B participates in fundamental processes that sustain cellular organization, signaling, and energy distribution.
KIF5B has attracted attention not only for its canonical cellular role but also for its involvement in human disease. In cancer, for example, aberrant fusion events that join KIF5B to growth-promoting kinases can create constitutively active oncogenic drivers. One notable fusion is KIF5B-RET, which has been identified in a subset of cancers and has implications for targeted therapy using RET inhibitors. Beyond cancer, disruption of kinesin-1–mediated transport is of interest in neurobiology because proper axonal and dendritic transport is essential for neuronal development, maintenance, and function. As a result, KIF5B sits at the crossroads of fundamental cell biology and translational medicine, illustrating how basic motor protein biology can intersect with clinical innovation.
Structure and function
KIF5B is a large, ATP-dependent motor protein that uses the energy from ATP hydrolysis to move along microtubules toward their plus ends. The protein is a member of the kinesin-1 family, which typically operates as a dimer and relies on its motor domain to bind microtubules and nucleotide cofactors. The motor domain resides in the N-terminal region and drives stepping along microtubules, while a coiled-coil stalk mediates dimerization and a C-terminal tail participates in cargo binding through interactions with kinesin light chains (KLC1-KLC4) and various adaptor proteins. The assembly of heavy chains with light chains forms a functional motor complex that recognizes diverse cargo through adaptor proteins such as Miro1 and TRAK1 in mitochondria-associated transport, as well as other cargo adaptors that direct vesicles, organelles, and synaptic components to distal cellular regions.
In neurons, kinesin-1 motors, including KIF5B, support the long-distance transport required for synaptic function and neuronal health. They operate in concert with dynein motors, which carry cargo in the opposite direction toward microtubule minus ends, enabling bidirectional trafficking within axons and dendrites. The activity of KIF5B is regulated by cargo availability, adaptor interactions, and signaling pathways that tune motor activity during development, synaptic plasticity, and response to cellular stress.
Gene, expression, and evolution
The KIF5B gene encodes the heavy chain of the kinesin-1 motor that is widely expressed in many tissues, with substantial expression in the brain and peripheral organs. Evolutionarily, KIF5B is one of several conserved kinesin-1 heavy chains in humans, a family that includes KIF5A and KIF5C. Each heavy chain can pair with kinesin light chains (KLC1-KLC4) to form functional motor complexes and to interpret a diverse set of cargo signals. The widespread expression of KIF5B reflects its essential role in general intracellular transport, not only in neurons but also in secretory cells, epithelial cells, and others.
Cargo and interactions
KIF5B binds a broad spectrum of cargoes through adaptor proteins and light chains. In mitochondria-associated transport, it collaborates with adaptors like Miro1 and TRAK1 to recruit mitochondria to the motor complex for delivery to energetic demand sites within neurites and other cellular compartments. Other cargos include lysosomes, endosomes, and synaptic vesicle precursors, illustrating the motor’s central role in maintaining cellular homeostasis and signaling by ensuring timely distribution of organelles and signaling intermediates.
Interactions with cargo adaptors are modulated by cellular context, developmental stage, and signaling cues. In neurons, proper KIF5B function supports axonal arborization, growth cone dynamics, and synaptic maintenance. Disruption in cargo binding or motor regulation can lead to transport defects that contribute to cellular stress, impaired signaling, and, in some contexts, neurodegenerative change.
Clinical significance
Cancer and gene fusions: A clinically important aspect of KIF5B biology is its involvement in oncogenic gene fusions. The KIF5B-RET fusion, in which the N-terminal portion of KIF5B is fused to the tyrosine kinase domain of RET, has been observed in non-small cell lung cancer and possibly other malignancies. This fusion constitutively activates RET signaling and promotes tumorigenesis, providing a rationale for targeted therapy with RET inhibitors such as pralsetinib and selpercatinib in fusion-positive cancers. The discovery of KIF5B-RET has influenced diagnostic approaches, with sequencing-based methods used to identify fusion-positive tumors and guide treatment decisions.
Neurological and developmental context: Given KIF5B’s central role in intracellular transport, defects in KIF5B function or regulation can impact neural development and neuronal maintenance. While many studies focus on model organisms to understand axonal transport, the direct contribution of KIF5B mutations to human neurodevelopmental disorders remains an area of active research. The broader importance of axonal and dendritic transport in neural health underscores why kinesin-1 motors, including KIF5B, are of enduring interest in neuroscience.
Therapeutic considerations and debates: The targeting of motor proteins and their pathways in disease raises questions about specificity and safety. Because kinesin-1 motors perform essential housekeeping functions in diverse cell types, therapeutic strategies must balance efficacy against the risk of widespread disruption of intracellular transport. In cancer, precision against driver fusions like KIF5B-RET offers a more selective route but also requires robust diagnostic testing to identify eligible patients. In neurodegenerative contexts, the prospect of modulating motor function as a therapeutic approach remains speculative and controversial, given potential off-target effects on normal cellular physiology.
Evolutionary and functional context
KIF5B is part of a conserved suite of molecular motors that coordinate intracellular logistics. Its function exemplifies the broader principle that long-range transport within cells is a prerequisite for cellular specialization, particularly in highly polarized cells. Comparative studies across species highlight both the conserved nature of kinesin-1–driven transport and species-specific adaptations in cargo selection and regulatory complexity.