KIF16B drives MT1-MMP recycling in macrophages and promotes co-invasion of cancer cells
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KIF16B drives MT1-MMP recycling in macrophages and promotes co-invasion of cancer cells. / Hey, Sven; Wiesner, Christiane; Barcelona, Bryan; Linder, Stefan.
In: LIFE SCI ALLIANCE, Vol. 6, No. 11, e202302158, 11.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - KIF16B drives MT1-MMP recycling in macrophages and promotes co-invasion of cancer cells
AU - Hey, Sven
AU - Wiesner, Christiane
AU - Barcelona, Bryan
AU - Linder, Stefan
N1 - © 2023 Hey et al.
PY - 2023/11
Y1 - 2023/11
N2 - The matrix metalloproteinase MT1-MMP is a central effector of cellular proteolysis. Accordingly, regulation of the surface-localized pool of MT1-MMP is crucial for cell migration and invasion. Here, we identify the superprocessive kinesin KIF16B as a major driver of fast recycling of MT1-MMP to the surface of primary human macrophages. KIF16B associates with MT1-MMP on Rab14-positive vesicles, and its depletion results in strongly reduced MT1-MMP surface levels, as shown by microscopical, biochemical, and cell-sorting approaches. As a consequence, KIF16B-depleted macrophages exhibit strongly reduced matrix degradation and invasion. We further identify the cargo-binding C-terminus of KIF16B as a critical element of MT1-MMP transport, as its overexpression uncouples MT1-MMP vesicles from the endogenous motor, thus leading to a reduction of surface-associated MT1-MMP and to reduced matrix degradation and invasion. Importantly, depletion of KIF16B in primary macrophages also reduces the co-invasion of cancer cells from tumor spheroids, pointing to the KIF16B-driven recycling pathway in macrophages as an important regulatory element of the tumor microenvironment.
AB - The matrix metalloproteinase MT1-MMP is a central effector of cellular proteolysis. Accordingly, regulation of the surface-localized pool of MT1-MMP is crucial for cell migration and invasion. Here, we identify the superprocessive kinesin KIF16B as a major driver of fast recycling of MT1-MMP to the surface of primary human macrophages. KIF16B associates with MT1-MMP on Rab14-positive vesicles, and its depletion results in strongly reduced MT1-MMP surface levels, as shown by microscopical, biochemical, and cell-sorting approaches. As a consequence, KIF16B-depleted macrophages exhibit strongly reduced matrix degradation and invasion. We further identify the cargo-binding C-terminus of KIF16B as a critical element of MT1-MMP transport, as its overexpression uncouples MT1-MMP vesicles from the endogenous motor, thus leading to a reduction of surface-associated MT1-MMP and to reduced matrix degradation and invasion. Importantly, depletion of KIF16B in primary macrophages also reduces the co-invasion of cancer cells from tumor spheroids, pointing to the KIF16B-driven recycling pathway in macrophages as an important regulatory element of the tumor microenvironment.
KW - Humans
KW - Matrix Metalloproteinase 14/genetics
KW - Macrophages
KW - Cell Movement/genetics
KW - Cell Separation
KW - Kinesins/genetics
KW - Neoplasms
KW - rab GTP-Binding Proteins/genetics
U2 - 10.26508/lsa.202302158
DO - 10.26508/lsa.202302158
M3 - SCORING: Journal article
C2 - 37696580
VL - 6
JO - LIFE SCI ALLIANCE
JF - LIFE SCI ALLIANCE
SN - 2575-1077
IS - 11
M1 - e202302158
ER -