Modulation of HeLa cells spreading by the non‐receptor tyrosine kinase ACK‐2

Coon, Melissa; Herrera, Román

doi:10.1002/jcb.10078

Cited by 14 publications

(18 citation statements)

References 43 publications

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“…We also find that Ack1 plays a role in cell migration, which is consistent with results obtained by van der Horst et al (30) who found that overexpression of Ack1 in cancer cell lines promoted a more invasive phenotype in vitro and in vivo. Our results are also consistent with those reported for Ack2; because overexpression of Ack2 results in increased migration of HeLa cells (25). Interestingly, most Ack1 effects on cell migration have been observed in highly migratory cell lines.…”

Section: Figure 5 Ack1 and P130supporting

confidence: 92%

“…Ack1 phosphorylates and activates Dbl, an exchange factor for Rho (22), as well as Ras/GRF1, an exchange factor for Ras (23). Ack1 also mediates p130Cas phosphorylation downstream of melanoma chondroitin sulfate proteoglycan (24), whereas Ack2 is implicated in modulating cell spreading, migration, and focal adhesion dynamics (20,25).Recent data demonstrate an important role for Ack1 in cancer cell survival (26 -28), as well as in tumor formation and metastasis (29 -31). MacKeigan et al (27) identified Ack1 as an anti-apoptotic gene in an RNAi screen targeted against human kinases, while Nur-e- Kamal et al (26) demonstrated that Ack1 is required for survival of v-Ras-transformed cells.…”

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confidence: 99%

“…Cas phosphorylation downstream of melanoma chondroitin sulfate proteoglycan (24), whereas Ack2 is implicated in modulating cell spreading, migration, and focal adhesion dynamics (20,25).…”

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Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130Cas

Modzelewska

Newman

Desai

et al. 2006

Journal of Biological Chemistry

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We previously showed that activation of the small GTPase Cdc42 promotes breast cell migration on a collagen matrix. Here we further define the signaling pathways that drive this response and show that Cdc42-mediated migration relies on the adaptor molecule p130Cas . Activated Cdc42 enhanced p130Cas phosphorylation and its binding to Crk. Cdc42-driven migration and p130 Cas phosphorylation were dependent on the Cdc42 effector Ack1 (activated Cdc42-associated kinase). Ack1 formed a signaling complex that also included Cdc42, p130Cas , and Crk, formation of which was regulated by collagen stimulation. The interaction between Ack1 and p130Cas occurred through their respective SH3 domains, while the substrate domain of p130 Cas was the major site of Ack1-dependent phosphorylation. Signaling through this complex is functionally relevant, because treatment with either p130Cas or Ack1 siRNA blocked Cdc42-induced migration. These results suggest that Cdc42 exerts its effects on cell migration in part through its effector Ack1, which regulates p130Cas signaling.Integrin-mediated cell interactions with components of the extracellular matrix regulate several aspects of both epithelial polarization and migration. Integrins are involved in signaling pathways that include activation of small GTPases, scaffolding molecules, and protein kinases (1-3). These signaling pathways regulate various aspects of cell migration on integrin ligands, such as collagen.Members of the Rho family of GTPases, Rho, Rac, and Cdc42, are important regulators of the actin cytoskeleton and have been shown to mediate cell migration (4 -10, for review see Refs. 3 and 11). Although much work has focused on understanding the mechanism by which Rho GTPases regulate the actin cytoskeleton, relatively less is known about the effects they have on integrin signaling pathways.Ack1 and Ack2 are homologous tyrosine kinases that bind exclusively to activated Cdc42-GTP, but not Rac or Rho (12, 13). The structure of Ack includes a kinase domain, an SH3 2 domain, a Cdc42/Rac-interactive binding (CRIB) domain, and a proline-rich C terminus, which is the key determinant between Ack1, a 120-kDa protein (12,14) and Ack2 an 83-kDa isoform (13). Multiple interactions have been identified for Ack1. In vitro binding to the proline-rich region has been demonstrated for Nck (15), Grb2 (16), Src (15), and Hck (17), whereas the SH3 domain binds HSH2, an adaptor in hematopoietic cells (18). Ack1 can also be co-immunoprecipitated with clathrin (16) and sorting nexin 9 (19), components of vesicle dynamics. Ack kinases have been implicated in a variety of signaling pathways. Tyrosine phosphorylation of Ack1 and Ack2 has been demonstrated downstream of growth factors (13, 16), cell adhesion (14, 20), and muscarinic receptors (21). Ack1 phosphorylates and activates Dbl, an exchange factor for Rho (22), as well as Ras/GRF1, an exchange factor for Ras (23). Ack1 also mediates p130Cas phosphorylation downstream of melanoma chondroitin sulfate proteoglycan (24), whereas Ack2 is implicated...

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Section: Figure 5 Ack1 and P130supporting

confidence: 92%

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confidence: 99%

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Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130Cas

Modzelewska

Newman

Desai

et al. 2006

Journal of Biological Chemistry

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“…The placement of the SH3 domain C-terminal to the catalytic domain is different from the other families of nonreceptor tyrosine kinases. ACK kinases are activated by cell adhesion, and they play important roles in cell spreading and motility (5)(6)(7). Recent work has also focused on the involvement of ACK kinases in signaling pathways leading to clathrin-mediated receptor endocytosis (8,9).…”

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Phosphorylation of WASP by the Cdc42-associated Kinase ACK1

Yokoyama

Lougheed

Miller

2005

Journal of Biological Chemistry

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ACK1 is a nonreceptor tyrosine kinase that associates specifically with Cdc42. Relatively few ACK1 substrates and interacting proteins have been identified. In this study, we demonstrated that ACK1 phosphorylates the Wiskott-Aldrich syndrome protein (WASP), a Cdc42 effector that plays an important role in the formation of new actin filaments. ACK1 and WASP interact in intact cells, and overexpression of ACK1 promotes WASP phosphorylation. Phosphorylation of WASP in vitro was enhanced by the addition of Cdc42 or phosphatidylinositol 4,5-biphosphate, presumably due to release of the autoinhibitory interactions in WASP. Surprisingly, when we mapped the sites of WASP phosphorylation, we found that ACK1 possesses significant serine kinase activity toward WASP (directed at Ser-242), as well as tyrosine kinase activity directed at Tyr-256. A serine peptide derived from the Ser-242 WASP phosphorylation site is also a substrate for ACK1. ACK1 expressed in bacteria retained its serine kinase activity, eliminating the possibility of contamination with a copurifying kinase. Serine phosphorylation of WASP enhanced the ability of WASP to stimulate actin polymerization in mammalian cell lysates. Thus, the tyrosine kinase ACK1 acts as a dual specificity kinase toward this substrate. In contrast to other dual specificity kinases that more closely resemble Ser/Thr kinases, ACK1 is a tyrosine kinase with an active site that can accommodate both types of hydroxyamino acids in substrates.The nonreceptor tyrosine kinase ACK1 2 (activated Cdc42-associated kinase-1) is a specific effector kinase for the GTP-bound form of Cdc42. ACK1 is a member of a distinct family of nonreceptor tyrosine kinases that includes ACK1, ACK2, and TNK in mammals and homologs in Drosophila and Caenorhabditis elegans (1, 2). The catalytic domain sequences of ACK family kinases are characteristic of tyrosine kinases, yet they are divergent from most other families of nonreceptor tyrosine kinases; they are most closely related to the epidermal growth factor receptor family kinases (3, 4). ACK kinases also have a unique structural organization; C-terminal to the catalytic domain, they possess SH3 domains, Cdc42-binding CRIB domains, and polyproline regions. The placement of the SH3 domain C-terminal to the catalytic domain is different from the other families of nonreceptor tyrosine kinases. ACK kinases are activated by cell adhesion, and they play important roles in cell spreading and motility (5-7). Recent work has also focused on the involvement of ACK kinases in signaling pathways leading to clathrin-mediated receptor endocytosis (8, 9).Relatively little is known about the physiological substrates of ACK kinases. Upon epidermal growth factor stimulation, ACK2 binds and phosphorylates sorting nexin 9 (SH3PX1), which promotes epidermal growth factor receptor degradation (9). In hematopoietic cells, ACK1 binds and phosphorylates the adaptor protein HSH2 (10). For both HSH2 and SH3PX1, ACK substrate recognition is governed by interactions with the noncatalytic r...

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“…ACK-1 was recently shown to interact with the SH3 domain of Hck, a member of the Src kinase family (22). Moreover, epidermal growth factor activates the ACK-1/Dbl pathway, where Dbl is involved in the regulation of cell migration (23)(24)(25), and the Drosophila orthologue of ACK-1 is involved in axonal guidance (26). These observations indicate an important role of ACK in transducing Ras-Cdc42 signals for various cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells

Nur‐E‐Kamal

Zhang

Keenan

et al. 2005

Molecular Cancer Research

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Activated Cdc42-associated kinase (ACK) has been shown to be an important effector molecule for the small GTPase Cdc42. We have shown previously an essential role for Cdc42 in the transduction of Ras signals for the transformation of mammalian cells. In this report, we show that the ACK-1 isoform of ACK plays a critical role in transducing Ras-Cdc42 signals in the NIH 3T3 cells. Overexpression of a dominant-negative (K214R) mutant of ACK-1 inhibits Ras-induced up-regulation of c-fos and inhibits the growth of v-Ras-transformed NIH 3T3 cells. Using small interfering RNA, we knocked down the expression of ACK-1 in both v-Ha-Ras-transformed and parental NIH 3T3 cells and found that down-regulation of ACK-1 inhibited cell growth by inducing apoptosis only in v-Ha-Ras-transformed but not parental NIH 3T3 cells. In addition, we studied the effect of several tyrosine kinase inhibitors and found that PD158780 inhibits the kinase activity of ACK-1 in vitro. We also found that PD158780 inhibits the growth of v-Ha-Ras-transformed NIH 3T3 cells. Taken together, our results suggest that ACK-1 kinase plays an important role in the survival of v-Ha-Ras-transformed cells, suggesting that ACK-1 is a novel target for therapies directed at Ras-induced cancer. (Mol Cancer Res 2005;3(5):297 -305)

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Modulation of HeLa cells spreading by the non‐receptor tyrosine kinase ACK‐2

Cited by 14 publications

References 43 publications

Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130Cas

Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130Cas

Phosphorylation of WASP by the Cdc42-associated Kinase ACK1

Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells

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