Dataset Information

1. SILAC based secretome analysis of WT and tKO cells

ABSTRACT: Integrins play a vital role in coordinating between the extracellular matrix (ECM) and the intracellular environment, thus enabling transduction of biomechanical signals to maintain tissue homeostasis. Here we investigate the significance of collagen-binding integrins in regulating fibroblast functions with relevance to fibrosis. Our data suggest that secretome from primary dermal fibroblasts isolated from mice lacking three collagen-binding integrins α1, α2 and α11 shows downregulation of several proteins essential for structure and regulation of crucial pro-fibrotic ECM components. In summary, abrogation of integrin-mediated cell-collagen association attenuates fibrosis.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin, Fibroblast

SUBMITTER: Prerana Wagle

LAB HEAD: Thomas Krieg

PROVIDER: PXD044683 | Pride | 2023-08-21

REPOSITORIES: Pride

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			Action	DRS
	20200816_Q2_UC_ColID_62_ProjID_2202_Krieg_01.raw	Raw
	20200816_Q2_UC_ColID_62_ProjID_2202_Krieg_02.raw	Raw
	20200816_Q2_UC_ColID_62_ProjID_2202_Krieg_03.raw	Raw
	20200816_Q2_UC_ColID_62_ProjID_2202_Krieg_04.raw	Raw
	20200816_Q2_UC_ColID_62_ProjID_2202_Krieg_05.raw	Raw

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Project description:MASTL (Microtubule associated serine-threonine kinase-like) is a relatively recently identified mitotic accelerator. There are also indications of its role in cancer progression, especially in breast cancer, but the molecular mechanisms behind this and the cell cycle independent functions of MASTL are poorly understood. Regulation of cell adhesion and actin dynamics play a central role in governing cell contractility, migration and cell division in normal and cancer cells. Here, we identify MASTL as regulator of cell contractility and activator of the transcriptional co-activator MTRF-A. We show that depletion of MASTL increases cell contact with the extracellular matrix, reduces contractile actin stress fibers in normal and breast cancer cells. Importantly, depletion of MASTL also leads to strongly impairs motility of breast cancer cells. Our transcriptome and proteome profiling revealed that depletion of MASTL impairs transcription and expression of several MRTF-A target genes implicated in cellular movement and actomyosin contraction, including Rho Guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and tropomyosin 4.2 (TPM4). Mechanistically, we find that MASTL is necessary for serum-induced activation of SRF/MTRF-A transcription and that exogenous expression of GEF-H1 in MASTL depleted cells is sufficient to restore cell contractility. Taken together, our results suggest that MASTL is a previously undescribed key regulator of cell morphology and the actin cytoskeleton through transcriptional control of multiple adhesion and actin cytoskeleton regulating genes with key roles in contractility, cell adhesion and migration. MASTL (Microtubule associated serine-threonine kinase-like) is a relatively recently identified mitotic accelerator. There are also indications of its role in cancer progression, especially in breast cancer, but the molecular mechanisms behind this and the cell cycle independent functions of MASTL are poorly understood. Regulation of cell adhesion and actin dynamics play a central role in cell migration, morphology and cancer progression, but the role of MASTL in these processes has not been evaluated. Here, we show that depletion of MASTL increases cell contact with the extracellular matrix in breast cancer cells. Importantly, depletion of MASTL also leads to reduction of contractile actin stress fibers and decreased cell motility. Further, our transcriptome and proteome profiling revealed that mechanistically depletion of MASTL impairs transcription and expression of regulators of cellular movement and actomyosin contraction, including Rho Guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and tropomyosin 4.2 (TPM4). Further, we show that the transcriptional changes are caused by defectiveness of the serum response factor (SRF) signalling. Importantly, this study reveals advanced role for MASTL in interphase cells that activates a transcriptional program strongly impacting on the expression of regulators of cellular motility and actomyosin contraction.

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1. SILAC based secretome analysis of WT and tKO cells

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