RACK1-mediated Integration of Adhesion and Insulin-like Growth Factor I (IGF-I) Signaling and Cell Migration Are Defective in Cells Expressing an IGF-I Receptor Mutated at Tyrosines 1250 and 1251

Kiely, Patrick A.; Leahy, Madeline; O׳Gorman, Denise M.; O’Connor, Rosemary

doi:10.1074/jbc.m412889200

Cited by 77 publications

(106 citation statements)

References 44 publications

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“…It has also been shown to be involved in migration of epithelia cells, partially through its interaction with PKC␤ or PKC , Src, and integrins (Buensuceso et al, 2001;McCahill et al, 2002;Buensuceso et al, 2005;Kiely et al, 2005;Doan and Huttenlocher, 2007). However, conflicting reports of RACK1 in either promoting or inhibiting cell migration are found in literature, probably reflecting the context-dependent functions of RACK1 in cells, tissues, and stimuli (Buensuceso et al, 2001;Doan and Huttenlocher, 2007).…”

Section: Discussionmentioning

confidence: 85%

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Chen

Lin

Shin

et al. 2008

MBoC

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Migration of cells up the chemoattractant gradients is mediated by the binding of chemoattractants to G protein-coupled receptors and activation of a network of coordinated excitatory and inhibitory signals. Although the excitatory process has been well studied, the molecular nature of the inhibitory signals remains largely elusive. Here we report that the receptor for activated C kinase 1 (RACK1), a novel binding protein of heterotrimeric G protein ␤␥ (G␤␥) subunits, acts as a negative regulator of directed cell migration. After chemoattractant-induced polarization of Jurkat and neutrophil-like differentiated HL60 (dHL60) cells, RACK1 interacts with G␤␥ and is recruited to the leading edge. Down-regulation of RACK1 dramatically enhances chemotaxis of cells, whereas overexpression of RACK1 or a fragment of RACK1 that retains G␤␥-binding capacity inhibits cell migration. Further studies reveal that RACK1 does not modulate cell migration through binding to other known interacting proteins such as PKC␤ and Src. Rather, RACK1 selectively inhibits G␤␥-stimulated phosphatidylinositol 3-kinase ␥ (PI3K␥) and phospholipase C (PLC) ␤ activity, due to the competitive binding of RACK1, PI3K␥, and PLC␤ to G␤␥. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with G␤␥-dependent activation of key effectors critical for chemotaxis.

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Section: Discussionmentioning

confidence: 85%

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Chen

Lin

Shin

et al. 2008

MBoC

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“…Moreover, RACK1 acts as a scaffolding protein to integrate adhesion and growth factor signaling necessary for cell migration. Interestingly, in cells expressing an IGF-IR mutant that is deficient in anti-apoptotic and transforming function, this scaffolding function of RACK1 is disrupted: RACK1 remains associated with b1 integrin but no longer associates with the IGF-IR, IRS-1, Shp2, Shc, or Src, and the cells no longer migrate (Kiely et al, 2005). Thus, disruption of this essential scaffolding function of RACK1 may inhibit cell migration and increase susceptibility to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…RACK1 is known to regulate integrin-mediated cell adhesion (Buensuceso et al, 2001;Hermanto et al, 2002;Kiely et al, 2002Kiely et al, , 2005Cox et al, 2003;Mamidipudi et al, 2004b;Vomastek et al, 2007). Moreover, RACK1 acts as a scaffolding protein to integrate adhesion and growth factor signaling necessary for cell migration.…”

Section: Discussionmentioning

confidence: 99%

A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways

Mamidipudi

Cartwright

2009

Oncogene

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Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G 1 and mitotic checkpoints. Here, we show that RACK1 also induces apoptosis of the cells, partly by inhibiting Src. In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X L , induces expression of proapoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates. Bax and Bim are required for RACK1-mediated mitochondrial cell death. RACK1-induced oligomerization of Bax is required for staurosporine-mediated cell death. RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway. This leads to activation of the transcription factor FOXO3, a potent inducer of apoptosis and G 1 arrest. Collectively, our results show that RACK1, partly by inhibiting Src, promotes mitochondrial cell death and blocks Akt-mediated cell survival. Thus, RACK1 inhibits growth and induces death of colon cells. Exploitation of these dual functions could lead to novel colon cancer therapies that mimic RACK1 function.

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“…PBK has also been reported to function as an MAPKK that can selectively interact with and phosphorylate p38 MAPK in vitro (Abe et al, 2000). The function of PBK in IGF-I or any growth-factor signalling pathway has not previously been established, although activation of p38 MAP kinase has been associated with IGF-I-mediated cell migration (Bartucci et al, 2001;Kiely et al, 2005) and with IGF-I-mediated repair from ultraviolet (UV)-induced DNA damage (Heron-Milhavet et al, 2001;Heron-Milhavet and LeRoith, 2002).…”

Section: Introductionmentioning

confidence: 99%

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

2006

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The contribution of the insulin-like growth-factor-I receptor (IGF-IR) to tumour progression is well documented. To identify new mediators of IGF-IR function in cancer, we recently isolated genes differentially expressed in cells overexpressing the IGF-IR. Among these was the serine/threonine kinase PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase), previously associated with highly proliferative cells and tissues. Here, we show that PBK is expressed at high levels in tumour cell lines compared with non-transformed cells. IGF-I could induce PBK expression only in transformed cells, whereas epidermal growth factor could induce PBK in non-transformed MCF-10A breast epithelial cells. Suppression of PBK expression using small interfering RNA did not prevent progression through the cell cycle, but caused decreased proliferation over time in culture, and reduced clonogenic growth in soft agarose. PBK knockdown impaired p38 activation after long-term stimulation with different growth factors and reduced DU145 cells motility. Suppressed PBK expression also resulted in an impaired response to DNA damage that was evident by the decreased generation of c-H2AX, increased DNA damage and decreased cell survival. Taken together, the data indicate that PBK is necessary for appropriate activation and function of the p38 pathway by growth factors. Thus, enhanced expression of PBK may facilitate tumour growth by mediating p38 activation and by helping cells to overcome DNA damage.

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RACK1-mediated Integration of Adhesion and Insulin-like Growth Factor I (IGF-I) Signaling and Cell Migration Are Defective in Cells Expressing an IGF-I Receptor Mutated at Tyrosines 1250 and 1251

Abstract: The scaffolding protein receptor for activated C kinase (RACK1) has been proposed to mediate the integration of insulin-like growth factor I receptor (IGF-IR) and adhesion signaling. Here we investigated the mechanism of this integration of signaling, by using an IGF-IR mutant (

Cited by 77 publications

References 44 publications

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

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