Open AccessDistinct forms of the actin cross-linking protein α-actinin support macropinosome internalization and trafficking
Author(s) -
Kevin M. Burton,
Katherine M. Johnson,
Eugene W. Krueger,
Gina L. Razidlo,
Mark A. McNiven
Publication year - 2021
Publication title -
molecular biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.463
H-Index - 225
eISSN - 1939-4586
pISSN - 1059-1524
DOI - 10.1091/mbc.e20-12-0755
Subject(s) - pinocytosis , internalization , microbiology and biotechnology , biology , membrane ruffling , actin cytoskeleton , actin remodeling , actin binding protein , actinin , endocytosis , invadopodia , actin , cytoskeleton , cell , cancer cell , biochemistry , cancer , genetics
The α-actinin family of actin cross-linking proteins have been implicated in driving tumor cell metastasis through regulation of the actin cytoskeleton; however, there has been little investigation into whether these proteins can influence tumor cell growth. We demonstrate that α-actinin 1 and 4 are essential for nutrient uptake through the process of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC) cells, and inhibition of these proteins decreases tumor cell survival in the presence of extracellular protein. The α-actinin proteins play essential roles throughout the macropinocytic process, where α-actinin 4 stabilizes the actin cytoskeleton on the plasma membrane to drive membrane ruffling and macropinosome internalization and α-actinin 1 localizes to actin tails on macropinosomes to facilitate trafficking to the lysosome for degradation. In addition to tumor cell growth, we also observe that the α-actinin proteins can influence uptake of chemotherapeutics and extracellular matrix proteins through macropinocytosis, suggesting that the α-actinin proteins can regulate multiple tumor cell properties through this endocytic process. In summary, these data demonstrate a critical role for the α-actinin isoforms in tumor cell macropinocytosis, thereby affecting the growth and invasive potential of PDAC tumors.