Abstract
Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members, the exact mechanism for the peripheral localization of APC remains unclear. Here we show that the heavy chain of kinesin-1 directly interacts with the APC C-terminus, contributing to the peripheral localisation of APC in fibroblasts. In rat hippocampal neurons the kinesin-1 binding domain of APC is required for its axon tip enrichment. Moreover, we demonstrate that APC requires interactions with both kinesin-2 and kinesin-1 for this localisation. Underlining the importance of the kinesin-1 association, neurons expressing APC lacking kinesin-1-binding domain have shorter axons. The identification of this novel kinesin-1-APC interaction highlights the complexity and significance of APC localisation in neurons.
Highlights
Neurons are highly polarised cells which require the structural and organisational capacity of the microtubule (MT) cytoskeleton and its associated proteins (MAPs)[1]
KIF5 directly binds a novel region in the Adenomatous polyposis coli (APC) C-terminus
We expressed the C-terminal cargo-binding tails of human KIF5A, B and C as GST-fusion proteins, and found that all were able to pull down endogenous APC from MRC-5 human fibroblast lysates (Fig. 1a)
Summary
Neurons are highly polarised cells which require the structural and organisational capacity of the microtubule (MT) cytoskeleton and its associated proteins (MAPs)[1]. APC functions through interactions with MTs, the MT plus end-interacting (+TIP) EB proteins, microtubule-based kinesin motors and both the actin and intermediate filament cytoskeletal elements[4,5,6,7,8,9,10,11]. Found at the tips of multiple neurites, APC becomes localised at the distal region of the growing axon, termed the growth cone, upon neuronal polarisation, perhaps in response to local inhibition of GSK3β13,22–29. At this site APC plays important roles in axonal growth, guidance, and morphology by promoting MT growth and stabilisation, actin remodelling and the translation of localised RNAs28,30–34. EB proteins associate with the C-terminus of APC, potentially enabling APC to track the growing plus end of MTs at the axon tip[4,31,33]
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