LASP1 in Cellular Signaling and Gene Expression: More than Just a Cytoskeletal Regulator

Figures

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  Figure 1. Graphic illustration of LASP1 domain structure. LASP1 consists of a LIM (LIN-11, Isl-1, and MEC-3) domain (red), two F-actin binding nebulin repeats (R1 and R2) (blue), a linker site with two key regulatory phosphorylation sites (S146 and Y171) (purple), and a SH3 (Src Homology 3) domain (green). The first nebulin repeat includes a nuclear export signal (NES) between residues 71–77 (yellow). Known domain-specific protein–protein interactions are provided.

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  Figure 2. LASP1 3D structure. Three-dimensional structure prediction of LASP1 highlighting sites at serine 146 and tyrosine 171. The structure was designed using Alphafold https://alphafold.ebi.ac.uk/entry/Q14847; accessed on 4 October 2022.

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  Figure 3. Phosphorylation-dependent regulation of LASP1 in TNBC. Function of LASP1 in TNBC cells is primarily regulated by its phosphorylation status at two specific sites, serine 146 (pS146) and tyrosine 171 (pY171). Unphosphorylated LASP1 primarily binds to F-actin and is complexed with other proteins such as zona occludens protein 2 (ZO2). Activation of protein kinase A (PKA) by either growth receptor signaling or Gαs pathways lead to phosphorylation of LASP1 at S146. pS146-LASP1 then preferentially binds to the C-terminal tail of chemokine receptor CXCR4 (implicated in breast cancer metastasis). Concurrently, pS146-LASP1 anchors AKT1 to the cell membrane serving as a scaffold and a facilitator of signaling between PTEN and mTORC2. Some pS146-LASP1 also dissociates from F-actin and is transported to the nucleus in a ZO2-dependent mechanism. Within the nucleus, pS146-LASP1 associates with proteins such as Snail1 which increases the stability of this transcriptional factor and promotes epithelial-to-mesenchymal transition through repression of epithelial markers such as E-cadherin. Once CXCR4 is activated, a fraction of LASP1 is preferentially phosphorylated at Y171 by phosphotyrosine…

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  Figure 4. LASP1-SH3 domain. Coulombic surface presentation of the LASP1-SH3 domain illustrating a negatively charged cleft and subsequent proline motif binding by conserved aromatic amino acids. The structure (PDB3i35) was designed using PyMol Molecular Graphic System Version 2.5.4 open source software (Schrödinger, LLC, New York, NY, USA): https://pymol.org; accessed on 12 October 2022.

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  Figure 5. LASP1, a Hub for Cancer Progression. LASP1 is a multifaceted protein in cancer progression and metastasis through several direct and indirect protein interactions. LASP1 binds to F-actin and is localized to actin rich protrusive structures such as invadopodia and lamellipodia, necessary for invasion and metastasis. Cancer cell viability and proliferation are promoted through activation of the PI3K/AKT signaling pathway, presumably through the LASP1 scaffolding function at the cell membrane. LASP1 plays a role in chemokine signaling by modeling CXCR4 stability, a receptor also overexpressed in several cancer entities. Nuclear LASP1 presence promotes metastasis by stabilizing Snail1 and enhancing epithelial-mesenchymal transition (EMT) and by remodeling chromatin to alter the transcriptome. Expression of mRNA is regulated by the interaction of LASP1 with Ago2, a protein of the RNA-induced silencing complex (RISC) and with eukaryotic initiation factor 4F complex (eIF4F) which induces translation of mRNA into oncoproteins. Created with BioRender software: https://biorender.com, accessed on 18 November 2022.