Abstract
Inhibition of the phospholipid phosphatase and tumor suppressor PTEN leads to excessive polarized cell growth during directed cell migration and neurite outgrowth. These processes require the precise regulation of both the actin and microtubule cytoskeleton. While PTEN is known to regulate actin dynamics through phospholipid modulation, whether and how PTEN regulates microtubule dynamics is unknown. Here, we show that depletion of PTEN leads to elevated levels of stable and post-translationally modified (detyrosinated) microtubules in fibroblasts and developing neurons. Further, PTEN depletion enhanced axon outgrowth, which was rescued by reducing the level of detyrosinated microtubules. These data demonstrate a novel role of PTEN in regulating the microtubule cytoskeleton. They further show a novel function of detyrosinated microtubules in axon outgrowth. Specifically, PTEN suppresses axon outgrowth by down-regulating the level of detyrosinated microtubules. Our results suggest that PTEN’s role in preventing excessive cell growth in cancerous and neurodevelopmental phenotypes is partially exerted by stabilization and detyrosination of the microtubule cytoskeleton.
Highlights
Tissue development and repair require the precise and local regulation of cytoskeletal dynamics to establish cell polarity for directed cell growth or migration
We tested whether depletion of PTEN lead to changes in the level of stable MTs in NIH/3T3 fibroblasts, a well-established system to quantify the formation of stable MTs by immunofluorescence label for the detyrosination of the C-terminus of alpha-tubulin [34,35,39]
Addition of lysophosphatidic acid (LPA) activates the pathway leading to an increase in the number of cells (> 80%) that score positive for detyrosinated MTs
Summary
Tissue development and repair require the precise and local regulation of cytoskeletal dynamics to establish cell polarity for directed cell growth or migration. The phospholipid phosphatase and tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) was previously identified as a negative regulator of cell motility [5,6,7]. While enhanced cell migration and proliferation are hallmarks of cancerous phenotypes in PTEN mutants, PTEN has emerged as a key regulator of neuronal development, with roles in a large variety of overgrowth and developmental disorders, including cancer and neuropathies [8,9,10,11]. The precise cellular mechanisms of how PTEN regulates polarized cell growth are unclear.
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