Emerging roles for LPP in metastatic cancer progression

Ngan, Elaine; Kiepas, Alexander; Brown, Claire M.; Siegel, Peter M.

doi:10.1007/s12079-017-0415-5

Cited by 24 publications

(26 citation statements)

References 174 publications

(266 reference statements)

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“…LPP is a member of the zyxin family of LIM proteins and is known to promote mesenchymal migration (38). LPP contains three LIM domains and a proline-rich aminoterminal region (PRR), which allow it to localize to adhesions and interact with numerous proteins (39). While loss of SHCA negatively impacts breast tumor initiation and growth (24), LPP is dispensable for primary tumor growth (37).…”

Section: Morementioning

confidence: 99%

“…LPP is a member of the zyxin family of LIM proteins (50). It is able to localize to adhesions and interact with LIM and SH3 protein (LASP), palladin, protein phosphatase 2A (PP2A), scrib, supervillin and vasodilator-stimulated phosphoprotein (VASP) (39). We have previously identified LPP as a promoter of efficient breast cancer lung metastasis (37).…”

Section: Shca Regulates Lpp Recruitment and Retention In Cellular Adhmentioning

confidence: 99%

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The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation

Kiepas

Voorand

Senécal

et al. 2020

Journal of Biological Chemistry

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SHC adaptor protein (SHCA) and lipoma-preferred partner (LPP) mediate transforming growth factor β (TGFβ)-induced breast cancer cell migration and invasion. Reduced expression of either protein diminishes breast cancer lung metastasis, but the reason for this effect is unclear. Here, using total internal reflection fluorescence (TIRF) microscopy, we found that TGFβ enhances the assembly and disassembly rates of paxillin-containing adhesions in an SHCA-dependent manner through the phosphorylation of the specific SHCA tyrosine residues Tyr-239, Tyr-240, and Tyr-313. Using a BioID proximity labeling approach, we show that SHCA exists in a complex with a variety of actin cytoskeletal proteins, including paxillin and LPP. Consistent with a functional interaction between SHCA and LPP, TGFβ-induced LPP localization to cellular adhesions depended on SHCA. Once localized to the adhesions, LPP was required for TGFβ-induced cell migration and adhesion dynamics. Mutations that impaired LPP localization to adhesions (mLIM1) or impeded interactions with the actin cytoskeleton via α-actinin (ΔABD) abrogated migratory responses to TGFβ. Live-cell TIRF microscopy revealed that SHCA clustering at the cell membrane precedes LPP recruitment. We therefore hypothesize that, in the presence of TGFβ, SHCA promotes the formation of small, dynamic adhesions by acting as a nucleator of focal complex formation. Finally, we defined a previously unknown function for SHCA in the formation of invadopodia, a process that also required LPP. Our results reveal that SHCA controls the formation and function of adhesions and invadopodia, two key cellular structures required for breast cancer metastasis.

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Section: Morementioning

confidence: 99%

Section: Shca Regulates Lpp Recruitment and Retention In Cellular Adhmentioning

confidence: 99%

The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation

Kiepas

Voorand

Senécal

et al. 2020

Journal of Biological Chemistry

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“…LPP (LIM domain containing preferred translocation partner in lipoma) is a member of the zyxin family of LIM proteins that is characterized as a promoter of mesenchymal/fibroblast cell migration. LPP has been shown to be a critical inducer of tumor cell migration, invasion and metastasis by virtue of its ability to localize to adhesions and to promote invadopodia formation (Ngan et al, 2018). A genome-wide association study of 253 Chinese individuals with B-cell NHL also identified a new susceptibility locus between BCL6 and LPP that was significantly associated with the increased risk of B-cell NHL (Tan et al, 2013).…”

Section: Literature Mining Consolidation Of Results and Selection Omentioning

confidence: 99%

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Srivastava

Galimberti

Kumar

et al. 2020

Front. Bioeng. Biotechnol.

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Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98,564, 170,550, and 113,654 variants which were reduced by pedigree-based filtering to 18,158, 465, and 26,465 in families I, II, and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites, and microRNA seed sequences were identified from upstream, downstream, 5 ′ and 3 ′ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2,383 potential candidate HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with Combined Annotation Dependent Depletion Tool (CADD) scores >20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of "Cancer, Hematological disease and Immunological Disease." We used the FCVPPv2 for further in silico analyses and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

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“…LPP (LIM domain containing preferred translocation partner in lipoma) is a member of the zyxin family of LIM proteins that is characterized as a promoter of mesenchymal/fibroblast cell migration. LPP has been shown to be a critical inducer of tumor cell migration, invasion and metastasis by virtue of its ability to localize to adhesions and to promote invadopodia formation (Ngan et al, 2018 (Loveday et al, 2011;Chen et al, 2018). The final selection of a candidate in this family will be based on further functional studies.…”

Section: Literature Mining Consolidation Of Results and Selection Ofmentioning

confidence: 99%

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Srivastava

Galimberti

Kumar

et al. 2019

Preprint

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Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98564, 170550 and 113654 variants which were reduced by pedigree-based filtering to 18158, 465 and 26465 in families I, II and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites and microRNA seed sequences were identified from upstream, downstream, 5 and 3 prime untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2383 high-risk HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with CADD (Combined Annotation Dependent Depletion Tool) scores > 20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of Cancer, Hematological disease and Immunological Disease. We used the FCVPPv2 for further in silico analysis and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

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Emerging roles for LPP in metastatic cancer progression

Cited by 24 publications

References 174 publications

The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation

The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

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