Phosphorylation of the small heat shock protein HspB1 regulates cytoskeletal recruitment and cell motility.

The small heat shock protein HspB1, also known as Hsp25/27, is a ubiquitously expressed molecular chaperone that responds to mechanical cues. Uniaxial cyclic stretch activates the p38 mitogen-activated protein kinase (MAPK) signaling cascade and increases the phosphorylation of HspB1. Similar to the mechanosensitive cytoskeletal regulator zyxin, phospho-HspB1 is recruited to features of the stretch-stimulated actin cytoskeleton. To evaluate the role of HspB1 and its phosphoregulation in modulating cell function, we utilized CRISPR/Cas9-edited HspB1-null cells and determined they were altered in behaviors such as actin cytoskeletal remodeling, cell spreading, and cell motility. In our model system, expression of WT HspB1, but not nonphosphorylatable HspB1, rescued certain characteristics of the HspB1-null cells including the enhanced cell motility of HspB1-null cells and the deficient actin reinforcement of stretch-stimulated HspB1-null cells. The recruitment of HspB1 to high-tension structures in geometrically constrained cells, such as actin comet tails emanating from focal adhesions, also required a phosphorylatable HspB1. We show that mechanical signals activate posttranslational regulation of the molecular chaperone, HspB1, and are required for normal cell behaviors including actin cytoskeletal remodeling, cell spreading, and cell migration.

Nuclear pore complexes concentrate on Actin/LINC/Lamin nuclear lines in response to mechanical stress in a SUN1 dependent manner.

Formation of robust actomyosin stress fibers (SF) in response to cell stretch plays a key role in the transfer of information from the cytoplasm into the nucleus. Actin/LINC/Lamin (ALL) nuclear lines provide mechanical linkage between the actin cytoskeleton and the lamin nucleoskeleton across the nuclear envelope. To understand the establishment of ALL lines, we used live cell imaging of cells exposed to cyclic stretch. We discovered that nuclear pore complexes (NPCs) concentrate along ALL lines that are generated in response to uniaxial cyclic stretch. The ALL-associated NPCs display increased fluorescence intensity of nucleoporins Pom121, TPR and Nup153 relative to nucleoporins that are distal to the ALL lines. Here we test the hypothesis that a LINC complex component of ALL lines, SUN1 is involved in the integration of NPCs with ALL lines. We generated CRISPR SUN1 knockdown and knockout cell lines and show that SUN1 is essential for normal integration of NPCs to ALL lines. Loss or elimination of SUN1 significantly diminishes NPC/ALL line integration, demonstrating a key role for SUN1 in the recruitment or stabilization of NPCs to a discrete subdomain of the nuclear envelope at ALL lines. This work provides new insight into the mechanism by which cells respond to mechanical force through nuclear envelope remodeling.

Genetic analyses in mouse fibroblast and melanoma cells demonstrate novel roles for PDGF-AB ligand and PDGF receptor alpha.

Platelet Derived Growth Factor Receptor (PDGFR) signaling is a central mitogenic pathway in development, as well as tissue repair and homeostasis. The rules governing the binding of PDGF ligand to the receptor to produce activation and downstream signaling have been well defined over the last several decades. In cultured cells after a period of serum deprivation, treatment with PDGF leads to the rapid formation of dramatic, actin-rich Circular Dorsal Ruffles (CDRs). Using CDRs as a robust visual readout of early PDGFR signaling, we have identified several contradictory elements in the widely accepted model of PDGF activity. Employing CRISPR/Cas9 gene editing to disrupt the Pdgfra gene in two different murine cell lines, we show that in addition to the widely accepted function for PDGFR-beta in CDR formation, PDGFR-alpha is also clearly capable of eliciting CDRs. Moreover, we demonstrate activity for heterodimeric PDGF-AB ligand in the vigorous activation of PDGFR-beta homodimers to produce CDRs. These findings are key to a more complete understanding of PDGF ligand-receptor interactions and their downstream signaling consequences. This knowledge will allow for more rigorous experimental design in future studies of PDGFR signaling and its contributions to development and disease.

Mechanosensing through Direct Binding of Tensed F-Actin by LIM Domains.

Mechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators. Here, we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding as a mechanosensing mechanism by which cytoskeletal tension can govern nuclear localization.

Mechanical stress triggers nuclear remodeling and the formation of transmembrane actin nuclear lines with associated nuclear pore complexes.

Mechanical stimulation of fibroblasts induces changes in the actin cytoskeleton including stress fiber (SF) reinforcement and realignment. Here we characterize the nuclear response to mechanical stimulation (uniaxial cyclic stretch). Using fluorescence microscopy and quantitative image analysis we find that stretch-induced nuclear elongation and alignment perpendicular to the stretch vector are dependent on formin-regulated actin polymerization. The mechanosensitive transcription factors Yes-associated protein/Transcriptional coactivator with PDZ domain (YAP/TAZ) and myocardin-related transcription factor (MRTF-A, also known as MKL1 and MAL1) accumulate in the nucleus and activate their target genes in response to uniaxial cyclic stretch. We show that transmembrane actin nuclear (TAN) lines are induced by stretch stimulation and nuclear envelope (NE) proteins including nesprins, SUN2, and lamins form Linkers of the Nucleoskeleton and Cytoskeleton (LINC) complexes aligned with actin SFs. These NE structures are altered by pharmacological treatments (Cytochalasin D and Jasplakinolide) or genetic disruption (zyxin gene deletion) that alter actin, and their persistence requires maintenance of stretch stimulation. Nuclear pore complexes (NPCs) accumulate at TAN lines providing a potential mechanism for linking mechanical cues to NPC function.

Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.

Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 µmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.

Mechanical signals activate p38 MAPK pathway-dependent reinforcement of actin via mechanosensitive HspB1.

Despite the importance of a cell's ability to sense and respond to mechanical force, the molecular mechanisms by which physical cues are converted to cell-instructive chemical information to influence cell behaviors remain to be elucidated. Exposure of cultured fibroblasts to uniaxial cyclic stretch results in an actin stress fiber reinforcement response that stabilizes the actin cytoskeleton. p38 MAPK signaling is activated in response to stretch, and inhibition of p38 MAPK abrogates stretch-induced cytoskeletal reorganization. Here we show that the small heat shock protein HspB1 (hsp25/27) is phosphorylated in stretch-stimulated mouse fibroblasts via a p38 MAPK-dependent mechanism. Phosphorylated HspB1 is recruited to the actin cytoskeleton, displaying prominent accumulation on actin "comet tails" that emanate from focal adhesions in stretch-stimulated cells. Site-directed mutagenesis to block HspB1 phosphorylation inhibits the protein's cytoskeletal recruitment in response to mechanical stimulation. HspB1-null cells, generated by CRISPR/Cas9 nuclease genome editing, display an abrogated stretch-stimulated actin reinforcement response and increased cell migration. HspB1 is recruited to sites of increased traction force in cells geometrically constrained on micropatterned substrates. Our findings elucidate a molecular pathway by which a mechanical signal is transduced via activation of p38 MAPK to influence actin remodeling and cell migration via a zyxin-independent process.

The actin regulator zyxin reinforces airway smooth muscle and accumulates in airways of fatal asthmatics.

Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms-and their failure in asthma-remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration. At the level of the cytoskeleton, zyxin facilitated repair at sites of stress fiber fragmentation. At the level of the isolated ASM cell, zyxin facilitated recovery of contractile force. Finally, at the level of the small airway embedded with a precision cut lung slice, zyxin slowed airway dilation. Thus, at each level zyxin stabilized ASM structure and contractile properties at current muscle length. Furthermore, when we examined tissue samples from humans who died as the result of an asthma attack, we found increased accumulation of zyxin compared with non-asthmatics and asthmatics who died of other causes. Together, these data suggest a biophysical role for zyxin in fatal asthma.

Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development.

EWS/FLI utilizes NKX2-2 to repress mesenchymal features of Ewing sarcoma.

In Ewing sarcoma, NKX2-2 is a critical activated target of the oncogenic transcription factor EWS/FLI that is required for transformation. However, its biological function in this malignancy is unknown. Here we provide evidence that NKX2-2 mediates the EWS/FLI-controlled block of mesenchymal features. Transcriptome-wide RNA sequencing revealed that NKX2-2 represses cell adhesion and extracellular matrix organization genes. NKX2-2-depleted cells form more focal adhesions and organized actin stress fibers, and spread over a wider area-hallmarks of mesenchymally derived cells. Furthermore, NKX2-2 represses the actin-stabilizing protein zyxin, suggesting that these morphological changes are attributable to zyxin de-repression. In addition, NKX2-2-knockdown cells display marked increases in migration and substrate adhesion. However, only part of the EWS/FLI phenotype is NKX2-2-dependent; consequently, NKX2-2 is insufficient to rescue EWS/FLI repression of mesenchymalization. Strikingly, we found that EWS/FLI-and NKX22-repressed genes are activated by ZEB2, which was previously shown to block Ewing sarcoma epithelialization. Together, these data support an emerging theme wherein Ewing sarcoma cells highly express transcription factors that maintain an undifferentiated state. Importantly, co-opting epithelial and mesenchymal traits by Ewing sarcoma cells may explain how the primary tumor grows rapidly while also "passively" metastasizing, without the need for transitions toward differentiated states, as in carcinomas.

A mechanical-biochemical feedback loop regulates remodeling in the actin cytoskeleton.

Cytoskeletal actin assemblies transmit mechanical stresses that molecular sensors transduce into biochemical signals to trigger cytoskeletal remodeling and other downstream events. How mechanical and biochemical signaling cooperate to orchestrate complex remodeling tasks has not been elucidated. Here, we studied remodeling of contractile actomyosin stress fibers. When fibers spontaneously fractured, they recoiled and disassembled actin synchronously. The disassembly rate was accelerated more than twofold above the resting value, but only when contraction increased the actin density to a threshold value following a time delay. A mathematical model explained this as originating in the increased overlap of actin filaments produced by myosin II-driven contraction. Above a threshold overlap, this mechanical signal is transduced into accelerated disassembly by a mechanism that may sense overlap directly or through associated elastic stresses. This biochemical response lowers the actin density, overlap, and stresses. The model showed that this feedback mechanism, together with rapid stress transmission along the actin bundle, spatiotemporally synchronizes actin disassembly and fiber contraction. Similar actin remodeling kinetics occurred in expanding or contracting intact stress fibers but over much longer timescales. The model accurately described these kinetics, with an almost identical value of the threshold overlap that accelerates disassembly. Finally, we measured resting stress fibers, for which the model predicts constant actin overlap that balances disassembly and assembly. The overlap was indeed regulated, with a value close to that predicted. Our results suggest that coordinated mechanical and biochemical signaling enables extended actomyosin assemblies to adapt dynamically to the mechanical stresses they convey and direct their own remodeling.

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Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma.

Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and α5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of α5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised.

Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth.

PURPOSE: Ewing sarcoma is a pediatric bone tumor that absolutely relies on the transcriptional activity of the EWS/ETS family of fusion oncoproteins. While the most common fusion, EWS/FLI, utilizes lysine-specific demethylase 1 (LSD1) to repress critical tumor suppressors, small-molecule blockade of LSD1 has not yet been thoroughly explored as a therapeutic approach for Ewing sarcoma. We therefore evaluated the translational potential of potent and specific LSD1 inhibition with HCI2509 on the transcriptional program of both EWS/FLI and EWS/ERG as well as the downstream oncogenic phenotypes driven by EWS/ETS fusions in both in vitro and in vivo models of Ewing sarcoma. EXPERIMENTAL DESIGN: RNA-seq was used to compare the transcriptional profiles of EWS/FLI, EWS/ERG, and treatment with HCI2509 in both EWS/FLI- and EWS/ERG-containing cell lines. We then evaluated morphologic phenotypes of treated cells with immunofluorescence. The induction of apoptosis was evaluated using caspase-3/7 activation and TUNEL staining. Colony forming assays were used to test oncogenic transformation and xenograft studies with patient-derived cell lines were used to evaluate the effects of HCI2509 on tumorigenesis. RESULTS: HCI2509 caused a dramatic reversal of both the up- and downregulated transcriptional profiles of EWS/FLI and EWS/ERG accompanied by the induction of apoptosis and disruption of morphologic and oncogenic phenotypes modulated by EWS/FLI. Importantly, HCI2509 displayed single-agent efficacy in multiple xenograft models. CONCLUSIONS: These data support epigenetic modulation with HCI2509 as a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins.

Integrin-ß5 and zyxin mediate formation of ventral stress fibers in response to transforming growth factor ß.

Cell adhesion to the extracellular matrix is an essential element of various biological processes. TGF-ß cytokines regulate the matrix components and cell-matrix adhesions. The present study investigates the molecular organization of TGF-ß-induced matrix adhesions. The study demonstrates that in various mouse and human epithelial cells TGF-ß induces cellular structures containing 2 matrix adhesions bridged by a stretch of actin fibers. These structures are similar to ventral stress fibers (VSFs). Suppression of integrin-ß5 by RNA interference reduces VSFs in majority of cells (> 75%), while overexpression of integrin-ß5 fragments revealed a critical role of a distinct sequence in the cytoplasmic domain of integrin-ß5 in the VSF structures. In addition, the integrity of actin fibers and Src kinase activity contribute to integrin-ß5-mediated signaling and VSF formation. TGF-ß-Smad signaling upregulates actin-regulatory proteins, such as caldesmon, zyxin, and zyxin-binding protein Csrp1 in mouse and human epithelial cells. Suppression of zyxin markedly inhibits formation of VSFs in response to TGF-ß and integrin-ß5. Zyxin is localized at actin fibers and matrix adhesions of VSFs and might bridge integrin-ß5-mediated adhesions to actin fibers. These findings provide a platform for defining the molecular mechanism regulating the organization and activities of VSFs in response to TGF-ß.

A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma.

Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.

LIM domains target actin regulators paxillin and zyxin to sites of stress fiber strain.

Contractile actomyosin stress fibers are critical for maintaining the force balance between the interior of the cell and its environment. Consequently, the actin cytoskeleton undergoes dynamic mechanical loading. This results in spontaneous, stochastic, highly localized strain events, characterized by thinning and elongation within a discrete region of stress fiber. Previous work showed the LIM-domain adaptor protein, zyxin, is essential for repair and stabilization of these sites. Using live imaging, we show paxillin, another LIM-domain adaptor protein, is also recruited to stress fiber strain sites. Paxillin recruitment to stress fiber strain sites precedes zyxin recruitment. Zyxin and paxillin are each recruited independently of the other. In cells lacking paxillin, actin recovery is abrogated, resulting in slowed actin recovery and increased incidence of catastrophic stress fiber breaks. For both paxillin and zyxin, the LIM domains are necessary and sufficient for recruitment. This work provides further evidence of the critical role of LIM-domain proteins in responding to mechanical stress in the actin cytoskeleton.

Elevated expression of the integrin-associated protein PINCH suppresses the defects of Drosophila melanogaster muscle hypercontraction mutants.

A variety of human diseases arise from mutations that alter muscle contraction. Evolutionary conservation allows genetic studies in Drosophila melanogaster to be used to better understand these myopathies and suggest novel therapeutic strategies. Integrin-mediated adhesion is required to support muscle structure and function, and expression of Integrin adhesive complex (IAC) proteins is modulated to adapt to varying levels of mechanical stress within muscle. Mutations in flapwing (flw), a catalytic subunit of myosin phosphatase, result in non-muscle myosin hyperphosphorylation, as well as muscle hypercontraction, defects in size, motility, muscle attachment, and subsequent larval and pupal lethality. We find that moderately elevated expression of the IAC protein PINCH significantly rescues flw phenotypes. Rescue requires PINCH be bound to its partners, Integrin-linked kinase and Ras suppressor 1. Rescue is not achieved through dephosphorylation of non-muscle myosin, suggesting a mechanism in which elevated PINCH expression strengthens integrin adhesion. In support of this, elevated expression of PINCH rescues an independent muscle hypercontraction mutant in muscle myosin heavy chain, Mhc(Samba1). By testing a panel of IAC proteins, we show specificity for PINCH expression in the rescue of hypercontraction mutants. These data are consistent with a model in which PINCH is present in limiting quantities within IACs, with increasing PINCH expression reinforcing existing adhesions or allowing for the de novo assembly of new adhesion complexes. Moreover, in myopathies that exhibit hypercontraction, strategic PINCH expression may have therapeutic potential in preserving muscle structure and function.

ZEB2 Represses the Epithelial Phenotype and Facilitates Metastasis in Ewing Sarcoma.

The vast majority of cancer-related deaths are attributable to metastasis. Effective treatment of metastatic disease will be improved by a better understanding of the molecular mechanisms contributing to this phenomenon. Much of the work in this field has focused on metastasis of carcinomas, tumors of epithelial origin, while metastasis of sarcomas, tumors of mesenchymal origin, remains poorly understood. Experimental evidence from studies in carcinomas, coupled with clinical observations, highlights the importance of both epithelial and mesenchymal characteristics in these cancer cells that make them competent for metastasis. We set out to test if similar cellular plasticity contributes to sarcoma metastasis. We found that the transcription factor, ZEB2, repressed epithelial gene expression in Ewing sarcoma cells, and this, in turn, repressed the epithelial phenotype. When ZEB2 was experimentally reduced in these cells, epithelial characteristics including decreased migratory ability and cytoskeleton rearrangements were observed. Furthermore, ZEB2 reduction in Ewing sarcoma cells resulted in a decreased metastatic potential using a mouse metastasis model. Our data show that Ewing sarcoma cells may have more epithelial plasticity than previously appreciated. This coupled with previous data demonstrating Ewing sarcoma cells also have mesenchymal features primes these cells to successfully metastasize. This is clinically relevant for 2 important reasons. First, this may offer a therapeutic opportunity to induce characteristics of one cell type or the other depending on the stage of the disease. Second, and more broadly, this raises questions about the cell of origin in Ewing sarcoma and may inform future animal models of the disease.

Lateral communication between stress fiber sarcomeres facilitates a local remodeling response.

Actin stress fibers (SFs) are load-bearing and mechanosensitive structures. To our knowledge, the mechanisms that enable SFs to sense and respond to strain have not been fully defined. Acute local strain events can involve a twofold extension of a single SF sarcomere, but how these dramatic local events affect the overall SF architecture is not believed to be understood. Here we have investigated how SF architecture adjusts to episodes of local strain that occur in the cell center. Using fluorescently tagged zyxin to track the borders of sarcomeres, we characterize the dynamics of resting sarcomeres and strain-site sarcomeres. We find that sarcomeres flanking a strain site undergo rapid shortening that directly compensates for the strain-site extension, illustrating lateral communication of mechanical information along the length of a stress fiber. When a strain-site sarcomere extends asymmetrically, its adjacent sarcomeres exhibit a parallel asymmetric shortening response, illustrating that flanking sarcomeres respond to strain magnitude. After extension, strain-site sarcomeres become locations of new sarcomere addition, highlighting mechanical strain as a trigger of sarcomere addition and revealing a, to our knowledge, novel type of SF remodeling. Our findings provide evidence to suggest SF sarcomeres act as strain sensors and are interconnected to support communication of mechanical information.