Liprin-α1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins

Asperti, Claudia; Astro, Veronica; Totaro, Antonio; Paris, Simona; Curtis, Iván de

doi:10.1242/jcs.054155

Cited by 60 publications

(89 citation statements)

References 27 publications

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“…V Astro et al (Figures 2g-i), thus confirming the effects of these proteins described in nontumorigenic COS7 cells (Asperti et al, 2009). On the other hand, LAR depletion had no detectable effects on invasion by MDA-MB-231 cells (Figure 2d).…”

Section: Regulation Of Tumor Cell Invasion By Liprin-a1supporting

confidence: 81%

“…MDA-MB-231 cells from ATCC (American type culture collection, Manassas, VA, USA) were used up to the tenth passage. Antibodies for liprin-a1 and bPIX have been characterized (Asperti et al, 2009). We utilized monoclonal antibodies against Flag and tubulin (Sigma-Aldrich, St Louis, MO, USA), GIT1/2 (BD Biosciences, San Jose, CA, USA) and cortactin (Millipore, Billerica, MA, USA); polyclonal antibodies against Flag (Sigma-Aldrich), GIT1 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and GFP (green fluorescent protein) (Molecular Probes, Eugene, OR, USA).…”

Section: Resultsmentioning

confidence: 99%

“…We utilized monoclonal antibodies against Flag and tubulin (Sigma-Aldrich, St Louis, MO, USA), GIT1/2 (BD Biosciences, San Jose, CA, USA) and cortactin (Millipore, Billerica, MA, USA); polyclonal antibodies against Flag (Sigma-Aldrich), GIT1 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and GFP (green fluorescent protein) (Molecular Probes, Eugene, OR, USA). siRNAs (from Invitrogen, Paisley, Scotland, UK or Qiagen, Hilden, Germany) for human liprin-a1 (liprins1a and b), human GIT2, human bPIX and control (luciferase) were as described (Frank et al, 2006;Asperti et al, 2009). The siRNA for human GIT1 targeted the sequence 5 0 -GCCTGGATGGAGACCTAGA-3 0 .…”

Section: Resultsmentioning

confidence: 99%

“…The siRNA for human GIT1 targeted the sequence 5 0 -GCCTGGATGGAGACCTAGA-3 0 . Cells transfected with Lipofectamine 2000 (Invitrogen) and 50-100 nM of siRNAs were used after 2 days for immunoblotting (Asperti et al, 2009). (c, d) MDA-MB-231 siRNA-transfected cells were tested for migration (c) and invasion (d).…”

Section: Resultsmentioning

confidence: 99%

“…Liprin-a1 is required for the assembly of neuronal synapses (Spangler and Hoogenraad, 2007) and is implicated in the regulation of non-neuronal cell migration (Shen et al, 2007). We have recently shown that liprin-a1 is an essential regulator of cell spreading on extracellular matrix (ECM) (Asperti et al, 2009(Asperti et al, , 2010. Interestingly, the gene for liprin-a1 is included in the human chromosomal region 11q13 (Katoh and Katoh, 2005;Ja¨rvinen et al, 2006) that is frequently amplified in various malignant tumors, including B20% of breast cancers (Al-Kuraya et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

et al. 2010

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Migration of cells and degradation of the extracellular matrix (ECM) are required for efficient tumor cell invasion, but the underlying molecular mechanisms are only partially known. The PPFIA1 gene for liprin-a1 is frequently amplified in human breast cancers. We recently demonstrated that liprin-a1 is an important regulator of cell edge dynamics during motility. We show, herein, that the liprin-a1 protein is highly expressed in human breast tumors. Functional analysis shows that liprin-a1 is specifically required for the migration and invasion of highly invasive human breast cancer MDA-MB-231 cells. We used time-lapse analysis to demonstrate defects in the motility of liprin-a1-depleted cells that include a striking instability of the lamellipodia. Liprin-a1 levels altered by either RNA interference or overexpression affected also cell spreading and the number of invadopodia per cell, but not the density of invadopodia per unit of surface area. On the other hand, silencing of liprin-a1 inhibited the degradation of the ECM, whereas its overexpression enhanced degradation, resulting in significant negative or positive effects, respectively, on the area of degradation per invadopodium. Transfection of fluorescent-labeled cortactin revealed that depletion of liprin-a1 also affected the assembly and disassembly of invadopodia, with decrease of their lifetime. Our results strongly support a novel important role of liprin-a1 in the regulation of human tumor cell invasion.

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Section: Regulation Of Tumor Cell Invasion By Liprin-a1supporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

et al. 2010

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Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity

Pehkonen,

Filippou,

Väänänen

et al. 2024

Molecular Oncology

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PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin‐α1, a member of the leukocyte common antigen–related protein tyrosine phosphatase (LAR‐RPTPs)‐interacting protein family. Liprin‐α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin‐α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression. The compounds with the highest differential responses between high PPFIA1‐expressing and silenced cells across cell lines were inhibitors targeting mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinases (ERK) signaling. KRAS proto‐oncogene, GTPase (KRAS)‐mutated MDA‐MB‐231 cells were more resistant to trametinib upon PPFIA1 knockdown compared with control cells. In contrast, liprin‐α1‐depleted HNSCC cells with low RAS activity showed a context‐dependent response to MEK/ERK inhibitors. Importantly, we showed that liprin‐α1 depletion leads to increased p‐ERK1/2 levels in all our studied cell lines independent of KRAS mutational status, suggesting a role of liprin‐α1 in the regulation of MAPK oncogenic signaling. Furthermore, liprin‐α1 depletion led to more pronounced redistribution of RAS proteins to the cell membrane. Our data suggest that liprin‐α1 is an important contributor to oncogenic RAS/MAPK signaling, and the status of liprin‐α1 may assist in predicting drug responses in cancer cells in a context‐dependent manner.

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Analyses of the spatiotemporal expression and subcellular localization of liprin‐α proteins

Zürner

Mittelstaedt

Dieck

et al. 2011

J of Comparative Neurology

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The members of the Liprin-α protein family, Liprin-α1-4, are scaffolding proteins that play important roles in the regulation of synapse assembly and maturation, vesicular trafficking, and cell motility. Recent evidence suggests that despite their high degree of homology, the four isoforms can be differentially regulated and fulfill diverging functions. However, to date their precise regional and subcellular distribution has remained elusive. Here, we examine the spatiotemporal expression patterns of Liprins-α in the rodent by using in situ hybridization, immunoblotting, and immunochemistry of primary cells as well as brain and retina sections. We show that Liprin-α1-4 mRNA and protein are widely expressed throughout the developing and adult central nervous system, with Liprin-α2 and -α3 being the major Liprin-α isoforms in the brain. Our data show that the four Liprin-α proteins differ in their regional distribution, in particular in the hippocampus, the cerebellum, and the olfactory bulb. Liprin-α1 exhibits a unique spatiotemporal expression pattern as its levels decrease during synaptogenesis, and it is the only Liprin-α with substantial non-neuronal expression. Immunocytochemistry of cultured primary neurons with pre- and postsynaptic marker proteins shows all four Liprins-α to be present at synapses and nonsynaptic sites to varying degrees. Together, these results show that neurons in different brain regions express a distinct complement of Liprin-α proteins.

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Liprin-α1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins

Cited by 60 publications

References 27 publications

Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity

Analyses of the spatiotemporal expression and subcellular localization of liprin‐α proteins

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