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

Abstract

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.

NDR1-Dependent Regulation of Kindlin-3 Controls High-Affinity LFA-1 Binding and Immune Synapse Organization

“…For example, a close correlation was detected between sites where microtubules and LFA-1 are clustered in IS of CTLs (59). It is possible that the association between RAPL and NDR1 with microtubules (60, 61) contributes to the stabilization of LFA-1/ICAM-1 to microtubules.…”

Aurora kinase inhibitors as anticancer molecules

“…These findings support the notion that under normal physiological conditions IκB Kinase2 positively regulates NF-κB but antagonizes Aurora-A signaling to ensure proper mitotic assembly and chromosome segregation while over expression of Aurora-A leads to derangement of this regulatory network. Furthermore, oncogenic effects of Aurora-A is also mediated through phosphorylation of RalA in the Ras signaling pathway (30,31) and the tumor suppressor NORE1A that functions as a regulatory node between Ras signaling and microtubule nucleation (32). Gain of function of Aurora-A, therefore, appears to be a seminal defect in cancer cells that can cause dual problems of aberrantly activating the Ras and the NF-κB signaling and also induction of abnormal mitotic spindle assembly.…”

RASSF tumor suppressor gene family: Biological functions and regulation

“…Required for apoptosis and growth inhibition [8] Inhibits MST2 activity [93] Modulates the MAP kinase signal downstream of the Ras signal [77] K-Ras [8] ST1, MST2 [177] MST1 [75] Not available 5A (Nore1A) 1q32 47.1 kDa Suppresses tumour growth via apoptosis induction or cell cycle delay [7,82] Regulates microtubule formation [182] Induces degradation of HIPK1 oncoprotein [183] Required for the TNFa mediated apoptosis and full activation of MST1 [80] Ras, Carma1 [182,184] MST1 [43,177] MST2 [177] tubulin, Aurora A [182] Mdm2 [183] Itch [185] Yes [80] resistant to TNFa-induced apoptosis, fail to activate Mst1 in vivo 5C (Nore1B, RAPL) 1q32 30.4 kDa…”