Dataset Information

Adipokine Leptin Co-operates With Mechanosensitive Ca^{2 +}-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

ABSTRACT: In postmenopausal women, a major risk factor for the development of breast cancer is obesity. In particular, the adipose tissue-derived adipokine leptin has been strongly linked to tumor cell proliferation, migration, and metastasis, but the underlying mechanisms remain unclear. Here we show that treatment of normal mammary epithelial cells with leptin induces EMT-like features characterized by higher cellular migration speeds, loss of structural ordering of 3D-mammo spheres, and enhancement of epithelial traction forces. Mechanistically, leptin triggers the phosphorylation of myosin light chain kinase-2 (MLC-2) through the interdependent activity of leptin receptor and Ca²⁺ channels. These data provide evidence that leptin-activated leptin receptors, in co-operation with mechanosensitive Ca²⁺ channels, play a role in the development of breast carcinomas through the regulation of actomyosin dynamics.

SUBMITTER: Acheva A

PROVIDER: S-EPMC7815691 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Adipokine Leptin Co-operates With Mechanosensitive Ca<sup>2 +</sup>-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

Acheva Anna A Kärki Tytti T Schaible Niccole N Krishnan Ramaswamy R Tojkander Sari S

Frontiers in cell and developmental biology 20210106

In postmenopausal women, a major risk factor for the development of breast cancer is obesity. In particular, the adipose tissue-derived adipokine leptin has been strongly linked to tumor cell proliferation, migration, and metastasis, but the underlying mechanisms remain unclear. Here we show that treatment of normal mammary epithelial cells with leptin induces EMT-like features characterized by higher cellular migration speeds, loss of structural ordering of 3D-mammo spheres, and enhancement of ...[more]

PMID: 33490070

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Project description:Stac protein (named for its SH3- and cysteine-rich domains) was first identified in brain 20 years ago and is currently known to have three isoforms. Stac2, Stac1, and Stac3 transcripts are found at high, modest, and very low levels, respectively, in the cerebellum and forebrain, but their neuronal functions have been little investigated. Here, we tested the effects of Stac proteins on neuronal, high-voltage-activated Ca2+ channels. Overexpression of the three Stac isoforms eliminated Ca2+-dependent inactivation (CDI) of l-type current in rat neonatal hippocampal neurons (sex unknown), but not CDI of non-l-type current. Using heterologous expression in tsA201 cells (together with β and α2-δ1 auxiliary subunits), we found that CDI for CaV1.2 and CaV1.3 (the predominant, neuronal l-type Ca2+ channels) was suppressed by all three Stac isoforms, whereas CDI for the P/Q channel, CaV2.1, was not. For CaV1.2, the inhibition of CDI by the Stac proteins appeared to involve their direct interaction with the channel's C terminus. Within the Stac proteins, a weakly conserved segment containing ∼100 residues and linking the structurally conserved PKC C1 and SH3_1 domains was sufficient to fully suppress CDI. The presence of CDI for l-type current in control neonatal neurons raised the possibility that endogenous Stac levels are low in these neurons and Western blotting indicated that the expression of Stac2 was substantially increased in adult forebrain and cerebellum compared with neonate. Together, our results indicate that one likely function of neuronal Stac proteins is to tune Ca2+ entry via neuronal l-type channels.SIGNIFICANCE STATEMENT Stac protein, first identified 20 years ago in brain, has recently been found to be essential for proper trafficking and function of the skeletal muscle l-type Ca2+ channel and is the site of mutations causing a severe, inherited human myopathy. In neurons, however, functions for Stac protein have remained unexplored. Here, we report that one likely function of neuronal Stac proteins is tuning Ca2+ entry via l-type, but not that via non-l-type, Ca2+ channels. Moreover, there is a large postnatal increase in protein levels of the major neuronal isoform (Stac2) in forebrain and cerebellum, which could provide developmental regulation of l-type channel Ca2+ signaling in these brain regions.

Dataset Information

Adipokine Leptin Co-operates With Mechanosensitive Ca^{2 +}-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

Publications

Adipokine Leptin Co-operates With Mechanosensitive Ca<sup>2 +</sup>-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

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Dataset Information

Adipokine Leptin Co-operates With Mechanosensitive Ca2 +-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

Publications

Adipokine Leptin Co-operates With Mechanosensitive Ca<sup>2 +</sup>-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Adipokine Leptin Co-operates With Mechanosensitive Ca^{2 +}-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells.