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J Biol Chem, Vol. 275, Issue 3, 2098-2102, January 21, 2000

G Protein Subunits Induce Stress Fiber Formation and Focal Adhesion Assembly in a Rho-dependent Manner in HeLa Cells^*

Hiroshi Ueda, Hiroshi Itoh^§, Junji Yamauchi^§, Rika Morishita, Yoshito Kaziro^§, Kanefusa Kato, and Tomiko Asano^¶

From the  Department of Biochemistry, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392 and the ^§ Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

In fibroblasts, the G protein  subunits G₁₂ and G₁₃ stimulate Rho-dependent stress fiber formation and focal adhesion assembly, whereas G protein subunits instead exert a disruptive influence. We show here that the latter can, however, stimulate the formation of stress fibers and focal adhesions in epithelial-like HeLa cells. Transient expression of ₁ with ₂, ₅, ₇, and ₁₂ in quiescent HeLa cells induced stress fiber formation and focal adhesion assembly as did expression of the constitutively active G₁₂. Co-expression of with G_i2 and the C-terminal fragment of the -adrenergic receptor kinase, both of which are known to bind and sequester free , blocked -induced stress fiber and focal adhesion formation. Inhibition was also noted with co-expression of a dominant negative mutant of Rho. Botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho, and a Rho-associated protein kinase inhibitor, Y-27632, similarly inhibited -induced stress fiber and focal adhesion assembly. These results indicate that G protein subunits regulate Rho-dependent actin polymerization in HeLa cells.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Rho family small GTP-binding proteins play a major role in regulating the actin polymerization necessary for cytoskeleton formation, determination of cell shape, and regulatory responses including chemotaxis and mitogenesis (1). In fibroblasts, the formation of stress fibers generally parallels the assembly of focal adhesions. For instance, some stimuli involving lysophosphatidic acid (LPA)¹, thrombin, and bombesin induce both. G proteins of the G₁₂ subfamily have been shown to be involved in Rho-dependent actin stress fiber formation and focal adhesion assembly stimulated by G protein-coupled receptors (2, 3). Recent reports have indicated that G₁₂ and G₁₃ are directly associated with p115 (4) and PDZ (5) guanine nucleotide exchange factors (GEF) for Rho, G₁₃ stimulating the guanine nucleotide exchange activity of p115-RhoGEF (4). RhoGEFs then activate Rho. In contrast to G₁₂ and G₁₃, microinjection of constitutively active forms of G_i2, G_q, and G₁₁ into fibroblasts does not induce stress fiber formation (2, 3). Furthermore, pertussis toxin does not inhibit LPA-induced stress fiber formation, suggesting uncoupling of this signal pathway to G proteins of the G_i/o subfamily (6).

G protein subunits regulate the c-Jun N-terminal kinase cascade through Rho family GTP-binding proteins such as Rac, Cdc42, and Rho (7, 8). This suggests the possibility that regulates Rho family GTP-binding proteins, leading to production of stress fibers and focal adhesions. However, microinjection of into quiescent Swiss 3T3 fibroblasts did not induce stress fiber formation (2). Furthermore, co-transfection of ₁ with ₂, ₅, or ₇ into CV-1 (9) and NIH 3T3 fibroblasts (10) did not remarkably change the stress fibers in medium containing serum, although a slight decrease was observed. In contrast to these slight effects of subunits, co-transfection of ₁₂ with ₁ into NIH 3T3 cells induced cell rounding, disruption of stress fibers, and enhancement of cell migration associated with specific phosphorylation of ₁₂ by protein kinase C (10, 11).

In this study, we transfected subunits into epithelial-like HeLa cells. Contrary to the results with fibroblasts, as well as G₁₂ induced stress fiber formation and focal adhesion assembly. We show here that subunits regulate Rho-dependent actin polymerization in HeLa cells.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Materials-- cDNAs of several  isoforms were prepared using synthetic polymerase chain reaction primers. cDNAs of bovine ₁ and ₂ were generously provided by M. I. Simon (California Institute of Technology) and T. Nukada (Tokyo Institute of Psychiatry), respectively, and subcloned into pCMV as described previously (12). cDNAs of RhoA and Rac1 were kindly provided by K. Kaibuchi (Nara Institute of Science and Technology) and Cdc42Hs cDNA by R. A. Cerione (Cornell University). All cDNAs of G protein subunits, FLAG-tagged dominant negative mutants of small GTP-binding proteins, and a C-terminal fragment (amino acids 495-689) of the -adrenergic receptor kinase (13) were subcloned into the pCMV5 vector as described previously (8, 12). The plasmid for the C3 exoenzyme was kindly provided by S. Narumiya (Kyoto University) (14), and that for the -opioid receptor was provided by C. Evans (UCLA) (15). Antibodies against the  and G_i2 subunits, generated by ourselves, have been described previously (16). Antibodies against G₁₂, G_s, G_q/11, and phosphotyrosine were obtained from Santa Cruz Biotechnology. Phospho-specific stress-activated protein kinase/c-Jun N-terminal kinase antibody was obtained from New England Biolabs, Inc. Mouse monoclonal antibody against vinculin was purchased from Sigma. Y-27632 (17) was supplied by Yoshitomi Pharmaceutical Industries.

Transfection and Staining-- HeLa cells were grown in Dulbecco's modified essential medium supplemented with 10% fetal bovine serum. Transient transfection was performed using LipofectAMINE Plus according to the manufacturer's instructions (Life Technologies, Inc.). The medium was replaced 24 h after transfection, and the cells were starved in serum-free medium for 24 h and then fixed in 4% paraformaldehyde in phosphate-buffered saline. Before fixation, transfected cells were treated with 20 µM Y-27632 for 2 h (17), with 150 µM tyrophostin A25, 10 µM tyrophostin AG 1478, 10 µM PP2, 30 µg/ml genistein, 1 µM Ro31-8220, 100 nM wortmannin or 50 µM LY-294002 for 3 h, or with 1 µM phorbol 12-myristate 13-acetate for 24 h. Fixed cells were immunostained using antibodies against , , and vinculin followed by secondary antibodies, fluorescein isothiocyanate-conjugated goat anti-rabbit IgG, and tetramethylrhodamine isothiocyanate-conjugated goat anti-mouse IgG, as described earlier (18). The cells were also stained for F-actin with tetramethylrhodamine isothiocyanate phalloidin (Sigma). After applying coverslips, slides were examined under a laser scanning microscope (FLUOVIEW Olympus) equipped for fluorescence. All experiments were performed at least three times with similar results.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Fig. 1 and 2 illustrate the effects of transient co-expression of ₁ with various  subunits, including ₂, ₅, ₇, and ₁₂ in quiescent HeLa cells. Combinations of ₁ with all individual  subunits stimulated the formation of thick stress fibers (Fig. 1) as well as focal adhesion assembly, as assessed by localization of vinculin at the leading edges and middle body in cells (Fig. 2). Such stress fibers and focal adhesions were not observed in expression-negative cells, which were seen among surrounding transfected cells (Figs. 1 and 2). Expression of the GTPase-deficient G₁₂ subunit (G₁₂Q229L) also induced actin stress fiber and focal adhesion assembly (Fig. 3, A, B, I, and J) as previously observed in Swiss 3T3 cells (2). However, the other GTPase-deficient  subunits, G_i2 (G_i2Q205L), G₁₁, (G₁₁Q209L), and G_s (G_sQ227L), were without such effects (Fig. 3, C-H), although G₁₁Q209L appeared to induce the formation of thin actin fibers because of bright staining of transfected cells with rhodamine phalloidin (Fig. 3, E and F). Activated G_i2 and G₁₁ were also ineffective in Swiss 3T3 cells (2, 3).

View larger version (70K): [in this window] [in a new window]   Fig. 1.   Induction of actin stress fiber formation by G protein subunits. HeLa cells were co-transfected with 1 and 2 (A and B), 5 (C and D), 7 (E and F), or 12 (G and H) and double-stained for  subunit (A, C, E, and G) and F-actin (B, D, F, and H). The results shown are representative of three independent experiments. Scale bar, 50 µm.

View larger version (71K): [in this window] [in a new window]   Fig. 2.   Induction of focal adhesion assembly by G protein subunits. HeLa cells were co-transfected with 1 and 2 (A and B), 5 (C and D), 7 (E and F), or 12 (G and H), and double-stained for  subunit (A, C, E, and G) and vinculin (B, D, F, and H). The results shown are representative of three independent experiments. Scale bar, 50 µm.

View larger version (63K): [in this window] [in a new window]   Fig. 3.   A GTPase-deficient mutant of G12 induces actin stress fiber formation and focal adhesion assembly, but other GTPase-deficient mutants of G protein  subunits do not. HeLa cells were transfected with G12Q229L (A, B, I, J), Gi2Q205L (C, D), G11Q209L (E, F), or GsQ227L (G, H) and double-stained for  subunits (A, C, E, G, I) and F-actin (B, D, F, H) or vinculin (J). The results shown are representative of three independent experiments. Scale bar, 50 µm.

In contrast with G₁₂Q229L subunits, it was reported that microinjection of into Swiss 3T3 cells (2) and transfection of into NIH 3T3 cells (10) did not stimulate stress fiber formation. In addition, NIH 3T3 cells, which were transfected with various subunits and cultured in the same conditions as HeLa cells in this study, did not induce stress fiber formation (data not shown). Therefore, the different responses to observed in HeLa cells and fibroblasts seem to be cell type differences rather than experimental differences.

Expression of ₁ or ₂ alone failed to stimulate the formation of actin stress fibers (data not shown), suggesting that complexes are necessary for this purpose. To test whether the complex is indeed involved in induction of stress fiber formation and focal adhesion assembly, we co-expressed G_i2 and the C-terminal fragment of the -adrenergic receptor kinase, both of which are expected to bind and sequester free , and showed this to prevent the ₁₂-induced actin stress fiber formation (Fig. 4, C and E) and focal adhesion assembly (Fig. 4, D and F). In contrast, G_i2 and the C-terminal fragment of the -adrenergic receptor kinase did not prevent G₁₂Q229L-induced stress fiber formation and focal adhesion assembly (data not shown).

View larger version (130K): [in this window] [in a new window]   Fig. 4.   Effects of Gi2 and the C-terminal fragment of the -adrenergic receptor kinase on -induced stress fiber formation and focal adhesion assembly. HeLa cells were co-transfected with 1 and 2 (A and B) plus Gi2 (C and D) or the C-terminal fragment of the -adrenergic receptor kinase (ARKct) (E and F) and stained for F-actin (A, C, and E) or vinculin (B, D, and F). Cells expressing the  subunit were identified by staining with the antibody as indicated by arrowheads. The results shown are representative of three independent experiments. Scale bar, 50 µm.

It is well known that actin stress fiber formation and focal adhesion assembly are induced by activation of Rho in several cells and tissues (1). To determine whether the effects of in HeLa cells were Rho-dependent, cells were co-transfected with ₁₂ and dominant negative mutants of Rho family GTP-binding proteins. As shown in Fig. 5 (A and B), co-transfection of RhoT19N completely inhibited -induced stress fiber formation and focal adhesion assembly. In contrast, co-transfection of dominant negative mutants of other Rho family GTP-binding proteins, Rac (RacT17N) and Cdc42 (Cdc42T17N), was without effect (Fig. 5, C-F). These dominant negative mutants seemed to be functional, because RacT17N and Cdc42T17N diminished the phosphorylation of c-Jun N-terminal kinase induced by LPA in HeLa cells (19) when the phosphorylation was determined by immunoblotting with phospho-specific c-Jun N-terminal kinase antibody (data not shown). G₁₂Q229L-induced stress fiber formation and assembly of focal adhesion was also inhibited by co-transfection of RhoT19N (data not shown). To confirm the Rho dependence, cells were co-transfected with ₁₂ and the botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho, or ₁₂-transfected cells were treated with Y-27632, a Rho-associated protein kinase (p160ROCK) inhibitor (17). In both cases, actin stress fiber formation and focal adhesion assembly were prevented (Fig. 5, G-J). These results clearly demonstrated that subunits regulate stress fiber formation and assembly of focal adhesion in a Rho and p160ROCK-dependent manner. The stimulation by expression of G₁₂Q229L was also prevented by C3 exoenzyme co-transfection and Y-27632 treatment (data not shown).

View larger version (93K): [in this window] [in a new window]   Fig. 5.   Effects of dominant negative mutants of the Rho family GTP-binding proteins, C3 exoenzyme, and Y-27632 on -induced actin stress fiber formation and focal adhesion assembly in HeLa cells. A-H, HeLa cells were co-transfected with 1 and 2 plus RhoT19N (A and B), RacT17N (C and D), Cdc42T17N (E and F), or C3 exoenzyme (G and H) and stained for F-actin (A, C, E, and G) or vinculin (B, D, F, and H). I and J, 12-transfected HeLa cells were incubated with 20 µM Y-27632 for 2 h and stained for F-actin (I) or vinculin (J). Cells expressing the  subunit were identified by staining with the antibody as indicated by arrowheads. The results shown are representative of three independent experiments. Scale bar, 50 µm.

A previous study showed the tyrosine kinase inhibitor tyrophostin A25 to inhibit the formation of stress fibers stimulated by LPA but not by constitutively active Rho in quiescent Swiss 3T3 cells, indicating the existence of a protein-tyrosine kinase acting in the LPA pathway upstream of Rho (20). Another study showed that tyrophostin A25 and tyrophostin AG 1478 inhibit the formation of stress fibers stimulated by constitutively active G₁₃Q226L but not by G₁₂Q229L (3). Therefore, we examined the effects of several kinds of tyrosine kinase inhibitors on ₁₂-transfected cells. Tyrophostin A25 (Fig. 6, C and D) and tyrophostin AG 1478 (data not shown) did not significantly influence the stress fiber formation and focal adhesion assembly induced by or G₁₂Q229L. Similarly, a selective inhibitor of the Src family of protein tyrosine kinases PP2 did not inhibit -induced stress fiber formation (data not shown). Although these tyrosine kinase inhibitors did not influence stress fiber formation, they effectively inhibited tyrosine kinases in the cells; tyrophostin A25 and PP2 decreased tyrosine phosphorylation of focal adhesion kinase-like protein (about 125 kDa) stimulated by G₁₂Q229L when phosphorylation was determined by antibody against phosphotyrosine (data not shown). Unlike these tyrosine kinase inhibitors, genistein blocked the formation of actin stress fibers stimulated by both and G₁₂Q229L (Fig. 6, E and F). These results suggested that genistein-sensitive but not tyrophostin-sensitive or Src-like tyrosine kinases are involved in the signaling with and G₁₂Q229L-induced Rho-dependent stress fiber formation.

View larger version (65K): [in this window] [in a new window]   Fig. 6.   Effects of various reagents on - or G12Q229L-induced stress fiber formation. HeLa cells were co-transfected with 1 and 2 (A, C, E, G-J) or transfected with G12Q229L (B, D, F) and treated with tyrophostin A25 (C, D), genistein (E, F), phorbol 12-myristate 13-acetate (G), Ro31-8220 (H), wortmannin (I), or LY-294002 (J), and stained for F-actin. Cells expressing the  or G12 subunit were identified by staining with the respective antibodies as indicated by arrowheads. The results shown are representative of three independent experiments. Scale bar, 50 µm. PKC, protein kinase C.

Because subunits can stimulate phospholipase C-, which results in up-regulation of protein kinase C (21, 22), we examined whether protein kinase C activation was required for the formation of actin stress fibers by . However, down-regulation of endogenous protein kinase C by a 24-h exposure of cells to 1 µM phorbol 12-myristate 13-acetate or treatment of cells with protein kinase C inhibitor Ro31-8220 for 3 h before fixation did not significantly inhibit -induced stress fiber formation (Fig. 6, G and H).

There have been several reports that G protein-coupled receptors, including LPA and muscarinic receptors, are linked with phosphatidylinositol 3-kinase in a -dependent fashion in cells (23, 24). To examine whether activation of phosphatidylinositol 3-kinase was required for -induced stress fiber formation, the cells were treated with the phosphatidylinositol 3-kinase inhibitors wortmannin and LY-294002 for 3 h before fixation. No inhibition was observed (Fig. 6, I and J). To verify that these inhibitors for protein kinase C and phosphatidylinositol 3-kinase and protein kinase C down-regulation actually inhibited the respective pathways, we determined effects of these treatments on the phosphorylation of c-Jun N-terminal kinase induced by LPA (25, 26). All inhibitors and protein kinase C depletion diminished the phosphorylation of c-Jun N-terminal kinase (data not shown), indicating that these treatments effectively inhibited these signaling pathways.

It is generally accepted that the -mediated signal pathway mainly acts through G_i/o-coupled receptors, and when cells were transiently transfected with cDNA encoding the -opioid receptor and stimulated by (D-Ala²,D-Leu⁵)enkephalin, stress fiber formation and focal adhesion assembly were induced (data not shown). However, co-transfection with the C-terminal fragment of the -adrenergic receptor kinase or treatment with pertussis toxin did not significantly block these effects. Thus -opioid receptors may couple not only with G_i/o but also with G₁₂ and G₁₃, for whose  subunits more effectively stimulate Rho than subunits in HeLa cells.

The present study clearly demonstrated that subunits, like G₁₂, regulate Rho-dependent actin polymerization, resulting in stress fiber formation and focal adhesion assembly in HeLa cells. Some recent reports have indicated that G₁₂ and G₁₃ are able to bind directly to p115-RhoGEF (4) or PDZ-RhoGEF (5) and that G₁₃ but not G₁₂ stimulates the GDP-GTP exchange reaction of p115-RhoGEF (4). Therefore, it is possible that subunits also directly interact with RhoGEF. In the budding yeast Saccharomyces cerevisiae, the complex has been shown to associate with Cdc24, a GEF for Cdc42, suggesting a cascade from to actin organization via Cdc42 (27, 28). The large number of RhoGEFs so far found share Dbl and pleckstrin homology domains (29). Some members of the family also have Src homology 2, Src homology 3, GTPase-activating protein, RasGEF ,and/or serine/threonine kinase domains, suggesting that they may interact with various molecules. In addition, analyses of the expression of RhoGEF family members have revealed that most are subject to varying degrees of tissue restriction (29). The different cell-specific responses to subunits observed in HeLa and NIH 3T3 cells may thus result from differential expression of the RhoGEF regulated by in these cells.

	ACKNOWLEDGEMENTS

We thank Drs. M. I. Simon, T. Nukada, S. Narumiya, C. Evans, K. Kaibuchi, and R. A. Cerione for supplying plasmids.

	FOOTNOTES

^* This work was partly supported by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan and by CREST.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, Institute for Developmental Research, Aichi Human Service Center, Kamiya-cho, Kasugai, Aichi 480-0392, Japan. Tel.: 81-568-88-0811; Fax: 81-568-88-0829; E-mail: toasano@inst-hsc.pref.aichi.jp.

	ABBREVIATIONS

The abbreviations used are: LPA, lysophosphatidic acid; G protein, guanine nucleotide binding regulatory protein; GEF, guanine nucleotide exchange factor.

	REFERENCES

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