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Time course of HGF and HGF/NK2 activation of MAPK. (a) Equal amounts of lysed cell protein were immunoprecipitated with anti-pY, and immunoblotted with anti-active MAPK. Phosphorylated p42 and p44 are indicated. (b) Equal amounts of protein from cell lysates were immunoprecipitated with anti-ERK1, and MAPK assays were performed as described in Experimental procedures. Mean values of 32 P-phosphorylation of MBP peptide (+s.e.m. from triplicate samples) from one representative experiment of three are expressed as CPM. 184B5 cells were serum-starved for 16 h before the addition of HGF (1 nM; squares) or HGF/NK2 (10 nM; circles) for the indicated times at 378C. 32D/c-Met cells were serum-starved for 4 h before the addition of HGF (2.7 nM; squares) or HGF/NK2 (3.7 nM; circles) for the indicated times at 378C
Source publication
HGF/NK2, a naturally occurring truncated HGF isoform, antagonizes the mitogenic and morphogenic activities of full length HGF, but stimulates cell scatter, or the motogenic response to HGF. We studied postreceptor signaling by these HGF isoforms in the human breast epithelial cell line 184B5, and in murine myeloid progenitor 32D cells transfected w...
Contexts in source publication
Context 1
... control for minor variations in gel loading, immunoblots were then stripped by incubating in 2% SDS+100 mM DTT in PBS for 2 h at 508C with multiple buer changes. The amount of p145 and p170 c-Met in each lane (panels labeledà-c-Met') was observed after blots were re-probed with anti-c-Met with chemiluminescent detection blots of lysates from control and HGF-treated 184B5 cells with an antibody against active MAPK revealed an increase in the levels of p44 and p42 detected within 3 min that peaked at 30 min (Figure 3a, left panel). After 60 min, the activation of both proteins had decreased, although both were still clearly activated relative to untreated control cells. ...
Context 2
... 60 min, the activation of both proteins had decreased, although both were still clearly activated relative to untreated control cells. The p44 and p42 MAPK activation pro®les observed by immunoblotting were consistent with the pro®le of MAPK activity observed in vitro after ERK1 immunoprecipitation from HGF-treated 184B5 cells (Figure 3b, left panel). In contrast, both assay methods showed that treatment of 184B5 cells with HGF/NK2 caused only transient MAPK activation, which peaked at 10 min and returned to control levels within 30 min (Figure 3a and b). ...
Context 3
... p44 and p42 MAPK activation pro®les observed by immunoblotting were consistent with the pro®le of MAPK activity observed in vitro after ERK1 immunoprecipitation from HGF-treated 184B5 cells (Figure 3b, left panel). In contrast, both assay methods showed that treatment of 184B5 cells with HGF/NK2 caused only transient MAPK activation, which peaked at 10 min and returned to control levels within 30 min (Figure 3a and b). In both assays, HGF/NK2-stimulated MAPK activation was also of lower magnitude than that observed in response to HGF. ...
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... general correlation between ligand-stimulated receptor and MAPK activation was also observed in 32D/c-Met cells. MAPK activation by either HGF isoform in 32D/c-Met was maximal at 10 min and declined thereafter (Figure 3a and b, right panels); MAPK activity in vitro was signi®cantly diminished after 20 min (Figure 3b, right panel). The markedly dierent temporal pro®les of HGF-stimulated MAPK activation in the two cell systems studied here suggest that HGF mitogenic potency is independent of the duration of MAPK activation. ...
Context 5
... general correlation between ligand-stimulated receptor and MAPK activation was also observed in 32D/c-Met cells. MAPK activation by either HGF isoform in 32D/c-Met was maximal at 10 min and declined thereafter (Figure 3a and b, right panels); MAPK activity in vitro was signi®cantly diminished after 20 min (Figure 3b, right panel). The markedly dierent temporal pro®les of HGF-stimulated MAPK activation in the two cell systems studied here suggest that HGF mitogenic potency is independent of the duration of MAPK activation. ...
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... markedly dierent temporal pro®les of HGF-stimulated MAPK activation in the two cell systems studied here suggest that HGF mitogenic potency is independent of the duration of MAPK activation. Most importantly, in this cell system HGF/NK2 stimulated almost sixfold higher MAPK activation than HGF (Figure 3a and b, right panels), which suggests that ligand-stimulated MAPK activation is not sucient for mitogenesis. ...
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Citations
... The TTA1 cell growth unsensitivity to MET pharmacological inactivation was further demonstrated with cabozantinib and crizotinib, despite the lower specificity of these multikinase inhibitors toward MET. The dissociation of the mitogenic activity from the proinvasive activity of MET was already demonstrated by the differential response of the human breast cell line 184B5 to the naturally occurring truncated HGF isoform, HGF/NK2 [35]. Indeed, HGF/NK2 induced cell motility, but not DNA synthesis, while MET and the downstream MAPK pathway were activated. ...
In thyroid cancers, MET receptor overexpression has been associated with higher risk of metastatic progression. In this study, it was shown that the anaplastic thyroid cancer (ATC)-derived TTA1 cell line overexpressed MET. By using FISH and relative quantification by qPCR, it was demonstrated that this overexpression resulted from a MET amplification with more than 20 copies. As expected, MET overexpression led to its constitutive activation and upregulated signaling towards the MAPK, PI3K/ AKT, STAT3 and NF-?B pathways. Since the usual feature of MET-amplified cell lines is the "MET addiction" for their cell proliferation, the effect of the highly selective ATP competitive MET inhibitor PHA665752 was analyzed. While PHA665752 strongly inhibited the MAPK pathway, it did not reduce cell proliferation in TTA1 cells (IC 50 = 4100 nM). This resistance to PHA665752 of the TTA1 cell line was demonstrated to be related to EGFR-MET functional cross-talk and PI3K/AKT and NF-?B signaling. Nevertheless, PHA665752 suppressed the anchorage-independent growth capacity of the TTA1 cell line and reduced cell migration and invasion in a transwell assay. The role of activated MET in these neoplastic properties of the TTA1 cells was also proved with si-MET-RNA targeting. Thus, this work highlights the TTA1 cell line as the first model of MET amplification in an ATC cell line, which leads to MET constitutive activation and underlies its neoplastic properties. Besides being a useful model for MET inhibitors screening, the TTA1 cell line also supports the argument for searching for MET amplification in ATC, as it could have therapeutic implications.
... NK1 facilitates cell proliferation, motility, and survival at lower efficacy than HGF [36]. In contrast, NK2 promotes cell migration but antagonized the mitogenic activity of HGF [37,38]. NK2 partially activates the MET receptor and is capable of inducing Y1234/1235 phosphorylation in the kinase domain but is incapable of inducing detectable levels of Y1349 phosphorylation in the docking site [39]. ...
... However, aML5-PEG11 induced AKT and ERK activation and promoted cell migration and invasion to a degree comparable to HGF. Because non-equivalent coupling between MET tyrosine phosphorylation levels and the activation of downstream signaling and biological responses is observed with the NK2 variant [37][38][39], this appears to be a defining characteristic of MET-mediated signal transduction that may reflect a switch-like response in downstream signaling upon receptor activation [40][41][42]. When receptor activation reaches a certain threshold, a small change in ligand-dependent receptor activation can cause a large change in the activity of a downstream effector and such hypersensitivity has been observed in the regulation of cellular responses [40][41][42]. ...
Non-native ligands for growth factor receptors with distinct chemical properties and different biological activities have the potential to become therapeutic applications. We previously generated MET/hepatocyte growth factor (HGF) receptor agonists using bivalent macrocyclic peptides. The highest MET-activating agonists exhibited biological activity that was indistinguishable from the effects of HGF. In this study, we investigated MET activation, signal characteristics, and biological responses induced by a macrocyclic peptide partial agonist known as aML5-PEG11. aML5-PEG11 induced weak tyrosine phosphorylation of MET while enhancing cell migration with potency comparable to HGF. aML5-PEG11 induced marked AKT (protein kinase B) and ERK (extracellular signal-regulated kinase) activation at a comparable potency and time-dependency to HGF, which suggests that enhancement of cell motility is attributable to activation of these molecules. In a 3-D culture of bile duct cancer cells in collagen gel, HGF induced robust activation of MET, ERK, and AKT, which was associated with enhanced expression of genes involved in bile duct development and subsequent branching of tubulogenesis. In contrast, aML5-PEG11 induced marginal activation of MET, ERK, and AKT (levels near the detection limits), which was associated with failure to enhance the expression of genes involved in bile duct development and a lack of tubulogenic response. Thus, MET activation by aML5-PEG11 couples to biological responses differently from HGF in an extracellular context-dependent manner.
... HGF or Nk1 bind and activate the Met transmembrane tyrosine kinase. Upon ligand binding, Met activates phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) through the Gab1/Grb2-SOSRas pathway [19,34]. The question we asked was how the Met-Fc binding deficiency in CHO-Neg cells due to reduced 6-O-sulfation and shorter HS chains on the cell surface impacted the HGF/Met or NK1/Met signaling at the cellular level. ...
Background/aims:
The up-regulation of hepatocyte growth factor/receptor, HGF/Met, signal transduction is observed in most of human cancers. Specific heparan sulfate structures enhance the HGF/Met signaling at both cell and animal-based model systems. Biochemical studies indicate that heparan sulfate interacts with HGF and a natural occurring splicing variant NK1 of HGF with similar affinity. However, it is currently unknown if cell surface heparan sulfate binds to Met at physiological conditions and if specific cell surface heparan sulfate structures are required for effective HGF/Met or NK1/Met signaling.
Methods:
An established flow sorting strategy was used to isolate a soluble Met recombinant protein-binding positive or negative CHO cell clones different only in specific heparan sulfate structures. The cell surface bindings were imaged by confocal microscopy and flow cytometry analysis. Glucosamine vs. galactosamine contents from media-, cell surface-, and cell association glycosaminoglycans were quantified by HPLC. 35S-sulfate labeled glycosaminoglycans were characterized by anion exchange and size-exclusion HPLC. Heparan sulfate disaccharide compositions were determined by HPLC-MS analysis. Western blot analyses of MAPK-p42/44 were used to monitor HGF- and NK1-facillated Met signaling.
Results:
CHO-Positive but not CHO-Negative cell surface heparan sulfate bound to Met recombinant protein and HGF/NK1 further promoted the binding. Overall glycosaminoglycan analysis results indicated that the CHO-Negative cells had reduced amount of heparan sulfate, shorter chain length, and less 6-O-sulfated disaccharides compared to that of CHO-Positive cells. Moreover, CHO-Negative cells were defective in NK1/Met but not HGF/Met signaling.
Conclusions:
This study demonstrated that soluble Met recombinant protein bound to cell surface HS at physiological conditions and a Met /HGF or NK1/HS ternary signaling complex might be involved in Met signaling. Shorter HS chains and reduced 6-O-sulfation might be responsible for reduced Met binding and the diminished NK1-initiated signaling in the CHO-Negative cells. The unique CHO-Positive and CHO-Negative cell clones established in current study should be effective tools for studying the role of specific glycosaminoglycan structures in regulating Met signaling. Such knowledge should be useful in developing glycosaminoglycan-based compounds that target HGF/Met signaling.
... The expression of HGF has been reported to be upregulated in various cancers and, thus, HGF is a potential serum marker for tumor diagnosis. [27][28][29] Here, we first checked HGF levels in both the tissues and sera of gastric cancer patients. The HGF protein was clearly increased in cancer tissues compared with adjacent tissues (Figure 1A,B). ...
Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNAs. HGF is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically down-regulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNAs.
... The β-chain has structural similarities to serine protease domains, however, lacks proteolytic activity, and contains a secondary receptor-binding site [21,22,30,31]. The truncated HGF isoform, NK1, contains the N-terminal hairpin and first kringle domain, whilst the NK2 variant also contains the second kringle domain [26,27,32]. NK1 is regarded as an agonist of the c-MET receptor, whilst NK2 is defined as a partial c-MET antagonist [28]. ...
... NK2 mRNA levels in DFs were also significantly higher than NK1. These results suggest support for the contrasting wound healing properties of OMFs and DFs (NK1 as essential for cellular proliferation, motility, and survival, whereas NK2 antagonises the mitogenic activity of HGF, pivotal to its anti-fibrotic functions) [27,32,50,51]. Furthermore, despite full-length HGF and the NK2 isoform having similar c-MET receptor affinities, only full-length HGF activates PI3K/Akt signalling responsible for stimulating mitogenic activity [28,32]. ...
... These results suggest support for the contrasting wound healing properties of OMFs and DFs (NK1 as essential for cellular proliferation, motility, and survival, whereas NK2 antagonises the mitogenic activity of HGF, pivotal to its anti-fibrotic functions) [27,32,50,51]. Furthermore, despite full-length HGF and the NK2 isoform having similar c-MET receptor affinities, only full-length HGF activates PI3K/Akt signalling responsible for stimulating mitogenic activity [28,32]. Taken together with the changes observed in this report, it appears that full-length HGF and the NK1 isoform were principally responsible for promoting the preferential proliferative, migratory and resistance to TGF-β 1 -driven fibroblast-myofibroblast differentiation properties of OMFs; although, the precise roles that downstream signalling pathways have in mediating these responses requires further investigation. ...
Oral mucosal wounds are characterized by rapid healing with minimal scarring, partly attributable to the “enhanced” wound healing properties of oral mucosal fibroblasts (OMFs).Hepatocyte growth factor (HGF) is a pleiotropic growth factor, with potential key roles in accelerating healing and preventing fibrosis. HGF can exist as full-length or truncated (HGF-NK), NK1 andNK2 isoforms. As OMFs display elevated HGF expression compared to dermal fibroblasts (DFs),this study investigated the extent to which HGF mediates the preferential cellular functions of OMFs, and the influence of pro-fibrotic, transforming growth factor-β1(TGF-β1) on these responses. Knockdown of HGF expression in OMFs by short-interfering RNA (siHGF) significantly inhibited OMF proliferative and migratory responses. Supplementation with exogenous TGF-β1 also significantly inhibited proliferation and migration, concomitant with significantly down-regulatedHGF expression. In addition, knockdown abrogated OMF resistance to TGF-β1-driven myofibroblast differentiation, as evidenced by increasedα-smooth muscle actin (α-SMA) expression, F-actin reorganisation, and stress fibre formation. Responses were unaffected in siHGF-transfected DFs.OMFs expressed significantly higher full-length HGF and NK1 levels compared to patient-matchedDFs, whilst NK2 expression was similar in both OMFs and DFs. Furthermore, NK2 was preferentially expressed over NK1 in DFs. TGF-β1supplementation significantly down-regulated full-length HGF and NK1 expression by OMFs, while NK2 was less affected. This study demonstrates the importance of HGF in mediating “enhanced” OMF cellular function. We also propose that full-length HGF andHGF-NK1 convey desirable wound healing properties, whilst fibroblasts preferentially expressing more HGF-NK2 readily undergo TGF-β1-driven differentiation into myofibroblasts.
... Other research showed that nimesulide also inhibits the activity and expression of aromatase in some breast cancer cell lines [7]. It has been reported that HGF dramatically increased the expression of COX2 in colorectal carcinoma cells, which might be mediated by two major signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, and it has been reported that COX2 is a vital downstream regulator of HGF [9]. ...
Hepatocyte growth factor (HGF) is a multifunctional growth factor that plays important roles in promoting the invasion and metastasis of various tumor cells. However, there are few reports about the exact mechanisms of HGF involved in the regulation of cell invasion via the induction of COX2. In this study, we found that HGF could activate its receptor c-Met and up-regulate COX2 expression in a dose- and time-dependent manner, which resulted in an increase in MMP-9 expression and subsequent invasiveness of the breast cancer cell lines MDA-MB-231 and MCF-7. The HGF-induced expression of COX2 and MMP-9 and cell invasion were partially suppressed by COX2 gene silencing. The PI3K/Akt and p38 MAPK signaling pathways were activated by HGF in both cell lines. However, PI3K/Akt or p38 MAPK-specific inhibition alone partially attenuated HGF-induced COX2 and MMP-9 expression and the invasiveness of the two breast cancer cell lines, and these HGF-induced effects were almost completely abolished by simultaneous treatment with both inhibitors. Therefore, we concluded that HGF mediates the up-regulation of COX2 predominantly through the PI3K/Akt and p38 MAPK signaling pathways, leading to MMP-9 expression and the subsequent invasion of two breast cancer cell lines. This study improves our understanding of the signal transduction mechanisms in the HGF-induced invasion and progression of breast cancer.
... Although we have not identified a specific microenvironmentderived factor that regulates transcription and metabolism in a paracrine manner, our previous work identified numerous secreted factors that are transcriptionally up-regulated during stromal activation in pancreatic cancer and that may serve to regulate transcription and metabolism in the epithelial compartment (15). These include factors that activate Ras-MAPK signaling via cell surface receptors to augment MYC activity, including connective tissue growth factor (39), hepatocyte growth factor (40), and insulinlike growth factor binding proteins 2, 3, and 7 (which signal to EGFR indirectly via sphingosine-1-phosphate) (41). Stromal PSCs also produce Il6, which can activate STAT3 in a paracrine manner to transcriptionally activate MYC (42)(43)(44) and induce associated metabolic and transcriptional changes. ...
Significance
Stromal fibroblasts of the pancreatic tumor microenvironment (TME) have been shown to play both tumor-supportive and tumor-suppressive roles in enacting a dysregulated wound-healing response. This apparent complexity suggests that an improved understanding of the molecular basis of cell–cell interactions in the TME is required to identify and target stroma-derived, growth-permissive mechanisms. Here we show that stromal cues induce transcriptional and metabolic changes in pancreatic cancer cells implicated in anabolic metabolism, which overlap with those previously demonstrated downstream of oncogenic Kras. Stromal signals broadly induce histone acetylation in the pancreatic cancer epigenome, and we highlight inhibition of acetyl-lysine sensing by the bromodomain and extraterminal (BET) bromodomain family, Bromodomain-containing protein 2 (BRD2) in particular, as a potential therapeutic strategy.
... NK1 was demonstrated to induce motility, survival, and proliferation, although its potency is lower than that of HGF [42]. In contrast, NK2 has motogenic activity but antagonizes the mitogenic activity of HGF [43,44], and probably thereby inhibits normal tissue repair in vivo and leading to increased fibrosis [45]. ...
... In transformed breast and lung epithelial cells, HGF has shown to stimulate cell motility and growth, while NK2 stimulated only motility but not growth [43]. How do these two isoforms trigger different responses by binding to and activating the same receptor? ...
... At first, we focused on mitogenic activity. In agreement with our previous findings [43,56], HGF stimulated proliferation of both BEpC and PAEC, whereas NK2 did not ( Fig. 3A and B). ...
Hepatocyte growth factor (HGF) is a pleiotrophic factor involved in cellular proliferation, migration and morphogenesis. HGF is required for normal tissue and organ development during embryogenesis, but in the adult HGF has been demonstrated to drive normal tissue repair and inhibit fibrotic remodeling. HGF has two naturally occurring human isoforms as a result of alternative splicing, NK1 and NK2. While NK1 has been defined as an agonist for HGF receptor, Met, NK2 is defined as a partial Met antagonist. Furthermore, under conditions of fibrotic remodeling, NK2 is still expressed while full length HGF is suppressed. Furthermore, the mechanism by which NK2 partially signals through Met is not completely understood. Here, we investigated the mitogenic, motogenic, and anti-apoptotic activities of NK2 compared with full length HGF in primary human bronchial epithelial cells (BEpC) and bovine pulmonary artery endothelial cells (PAEC). In human BEpC, NK2 partial activated Met, inducing Met phosphorylation at Y1234/1235 in the tyrosine-kinase domain but not at Y1349 site in the multifunctional docking domain. Partial phosphorylation of Met by NK2 resulted in activation of MAPK and STAT3, but not AKT. This correlated with motogenesis and survival in a MAPK-dependent manner, but not cell proliferation. Overexpression of a constitutively active AKT complemented NK2 signaling, allowing NK2 to induce cell proliferation. These data indicate that NK2 and HGF drive motogenic and anti-apoptotic signaling but only HGF drives cell proliferation by activating AKT-pathway signaling. These results have implications for the biological consequences of differential regulation of the two isoforms under pro-fibrotic conditions.
... Like full-length HGF, NK1 stimulates mitogenesis, motogenesis and morphogenesis, although at reduced potency and with greater HSP dependence [9,[17][18][19][20]. In contrast, NK2 can competitively antagonize mitogenicity stimulated by HGF or NK1 [6,18,19], but retains potent motogenic and invasive activity in vitro [18,19] and strongly promotes HGF-driven tumor metastasis in vivo [21], activating the MET kinase and many of the same intracellular signaling pathways activated by HGF and NK1 [22]. ...
... Purified HGF and MET recombinant proteins, and antibodies against MET and HGF, were from R&D Systems; specific anti-phospho-receptor antibodies or 4G10 were from Millipore. The cell lines PC3M, PC3M-luc, B5/589, U87 MG, SK-LMS-1, 786-0, UOK161, UOK109, UOK122, UOK150, J82, RT-4 and SW780 were cultured as described [6,7,9,17,18,20,22]. NK1 3S protein was recombinantly expressed and purified as described [20]. ...
Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. Here we show that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival.
... Additionally, the active form of HGF has been reported to be released in the extracellular matrix where it undergoes enzymolysis by matrix metalloproteinases induced by mechanical stimulation such as stretch stimulation and/or muscle injury [22][23][24] . HGF-bound c-Met is tyrosine-phosphorylated, and mediates mitogenesis and morphogenesis 25) . In the present study, the HGF-α antibody recognized both the active and inactive forms of HGF, and the anti-phospho-tyrosine antibody did not recognize phospho-c-Met. ...
[Purpose] The present study aimed to determine the effects of short muscle strength exercise on hepatocyte growth factor expression and satellite cell activation. [Subjects] The study included 72 2-12-week-old male Sprague-Dawley rats. [Methods] The rat plantaris muscle was contracted with a 5-min electrical stimulation of the sciatic nerve, and then, the mRNA expressions of hepatocyte growth factor and myogenic regulatory factors in the plantaris muscle were determined, and the phosphorylation of the hepatocyte growth factor receptor (c-Met) was examined. [Results] The mRNA expressions of hepatocyte growth factor and myogenic regulatory factors increased after a short muscle contraction compared to that un-contraction. Immunofluorescence analysis showed the expression of hepatocyte growth factor protein and the possibility that downstream biological changes occurred in the hepatocyte growth factor-bound c-Met. [Conclusion] Our results demonstrated that activation of satellite cells induced hepatocyte growth factor expression during muscle contraction with a short 5-min electrical stimulation, which simulates short muscle strength exercise in physical therapy. The present study provides evidence for the use of short muscle strength exercise in physical therapy.
