RASSF1A interacts with and activates the mitotic kinase Aurora-A

Liu, L; Guo, Cai; Dammann, Reinhard; Tommasi, Stefania; Pfeifer, Gerd P.

doi:10.1038/onc.2008.220

Cited by 29 publications

(22 citation statements)

References 68 publications

(104 reference statements)

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“…The existence of a possible feedback mechanism was implied in a recent report suggesting that RASSF1A is an activator of Aurora A in vivo; however, this mechanism was not shown to occur in vitro (47). In fact, we also found no evidence for activation of Aurora A by RASSF1A in an in vitro kinase assay (data not shown).…”

Section: Discussioncontrasting

confidence: 34%

Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity

Song

Kim

et al. 2009

Cancer Research

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The Aurora (Ipl) kinase family plays important roles in the regulation of mitosis and tumorigenesis. The tumor suppressor RASSF1A controls mitotic progression by regulating anaphase-promoting complex (APC)-Cdc20 activity and microtubule stability, but the mechanism by which this action is regulated has not been previously established. Here, we show that Aurora A and B associate with and phosphorylate

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Section: Discussioncontrasting

confidence: 34%

Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity

Song

Kim

et al. 2009

Cancer Research

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“…NORE1A Interacts with Aurora A Kinase-It has been reported recently that RASSF1A interacts with Aurora A in vitro and in transfected cells (13,14,23). We have found that NORE1A is also capable of interacting with Aurora A kinase in transfected 293 cells (Fig.…”

Section: Volume 285 • Number 21 • May 21 2010supporting

confidence: 54%

Growth and Tumor Suppressor NORE1A Is a Regulatory Node between Ras Signaling and Microtubule Nucleation

Bee

Moshnikova

Mellor

et al. 2010

Journal of Biological Chemistry

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NORE1A is a Ras-binding protein that belongs to a group of tumor suppressors known as the Ras association domain family. Their growth-and tumor-suppressive function is assumed to be dependent on association with the microtubule cytoskeleton. However, a detailed understanding of this interplay is still missing. Here, we show that NORE1A directly interacts with tubulin and is capable of nucleating microtubules. Strikingly, the ability to stimulate nucleation is regulated in a dual specific way either via phosphorylation of NORE1A within the Ras-binding domain by Aurora A kinase or via binding to activated Ras. We also demonstrate that NORE1A mediates a negative effect of activated Ras on microtubule nucleation. On the basis of our results, we propose a novel regulatory network composed of the tumor suppressor NORE1A, the mitotic kinase Aurora A, the small GTPase Ras, and the microtubule cytoskeleton.

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“…Pan-PP1 siRNA (for the ␣-, ␤-, and ␥-isoforms; sc-43545) was obtained from Santa Cruz Biotechnology. RASSF1A siRNA 196 has been described previously (31). The siRNA oligonucleotides were delivered into HeLa cells using Lipofectamine 2000 (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

The Tumor Suppressor RASSF1A Prevents Dephosphorylation of the Mammalian STE20-like Kinases MST1 and MST2

Guo

Zhang

Pfeifer

2011

Journal of Biological Chemistry

103

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The RASSF1A tumor suppressor protein interacts with the pro-apoptotic mammalian STE20-like kinases MST1 and MST2 and induces their autophosphorylation and activation, but the mechanism of how RASSF1A activates MST1/2 is unclear. Okadaic acid treatment and PP2A knockdown promoted MST1/2 phosphorylation. Data from dephosphorylation assays and reduced activation of MST1/2 seen after RASSF1A depletion suggest that dephosphorylation of MST1/2 on Thr-183 and Thr-180 by PP2A is prevented by RASSF1A, shifting the balance of MST1/2 to the activated autophosphorylated form. In addition to preventing dephosphorylation, RASSF1A also stabilized the MST2 protein. Through binding to MST1/2, RASSF1A supports maintenance of MST1/2 phosphorylation, promoting an active state of the MST kinases and favoring induction of apoptosis. This is one of the first examples of a tumor suppressor acting as an inhibitor of a specific dephosphorylation pathway.The RASSF1A (Ras association domain family 1 isoform A) gene is localized on chromosome 3p21.3, in an area that likely harbors at least one important tumor suppressor gene (1, 2). RASSF1A is frequently silenced by promoter hypermethylation in many human tumors (3, 4). Rassf1a-targeted mice are prone to spontaneous and carcinogen-induced tumorigenesis (5, 6). The RASSF1A protein is involved in several growth regulatory and pro-apoptotic pathways. Recent work has shown that RASSF1A associates with components of the mammalian Hippo signaling network (7), an emerging pathway implicated in organ size control, restriction of cell proliferation, apoptosis, and tumor suppression (8 -10). RASSF1A interacts with the mammalian kinases MST1 and MST2, the orthologs of the Drosophila Hippo kinase, and activates MST1 and MST2 by promoting their autophosphorylation and phosphorylation of the downstream LATS1 kinase (7).The mammalian Sterile-20-like kinases MST1 (also known as STK4 and KRS2) and MST2 (also known as STK3 and KRS1) belong to the class II germinal center (Ser/Thr protein) kinases (11). MST1 and MST2 have recently been implicated as important tumor suppressors (12)(13)(14), suggesting that the RASSF-MST complexes may represent intriguing tumor-suppressing modules. Besides their potential role in promoting apoptosis through the Hippo pathway, MST1 and MST2 are implicated in several other pro-apoptotic processes. During induction of apoptosis, MST1 and MST2 can be activated, leading to phosphorylation of histone H2B and nuclear DNA fragmentation (15). In addition, the activation of JNK (Jun N-terminal kinase) signaling (16, 17) and phosphorylation of FOXO3 transcription factors (18) have also been associated with MST-induced apoptosis.The MST1 and MST2 kinases are regulated by several mechanisms, including phosphorylation, caspase cleavage, dimerization, and cofactors (19). They are activated in response to staurosporine (STS), 2 a potent protein kinase C inhibitor and apoptosis inducer, or the protein phosphatase inhibitor okadaic acid (20). Several other pro-apoptotic stimuli and stresses hav...

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RASSF1A interacts with and activates the mitotic kinase Aurora-A

Cited by 29 publications

References 68 publications

Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity

Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity

Growth and Tumor Suppressor NORE1A Is a Regulatory Node between Ras Signaling and Microtubule Nucleation

The Tumor Suppressor RASSF1A Prevents Dephosphorylation of the Mammalian STE20-like Kinases MST1 and MST2

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