SRC Kinase-Mediated Tyrosine Phosphorylation of TUBB3 Regulates Its Stability and Mitotic Spindle Dynamics in Prostate Cancer Cells

Alfano, Alan P.; Xu, Jin; Yang, Xi; Deshmukh, Dhanraj; Qiu, Yun

doi:10.3390/pharmaceutics14050932

Cited by 8 publications

(6 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although SRC kinases are primarily implicated in mitogenic signaling, there is also evidence that they can modulate mitosis. SRC‐family kinases modulate microtubule polymerization rates [ 102 , 109 ], a process where TPX2 also has an important role. Similarly, v‐SRC expression overrides the spindle assembly checkpoint leading to chromosome missegregation [ 91 , 110 ].…”

Section: Discussionmentioning

confidence: 99%

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

Marugán,

Sanz‐Gómez,

Ortigosa

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN‐positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN‐associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto‐oncogene c‐Src (SRC) inhibitor dasatinib due to activation of the Yes‐associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer‐derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

Marugán,

Sanz‐Gómez,

Ortigosa

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

show abstract

“…Although SRC kinases are primarily implicated in mitogenic signaling, there is also evidence that they can modulate mitosis. SRCfamily kinases modulate microtubule polymerization rates [102,109], a process where TPX2 also has an important role. Similarly, v-SRC expression overrides the spindle assembly checkpoint leading to chromosome missegregation [91,110].…”

Section: -Discussionmentioning

confidence: 99%

TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling

Marugán,

Ortigosa,

Sanz-Gómez

et al. 2023

Preprint

View full text Add to dashboard Cite

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of TPX2 enhances sensitivity to the SRC inhibitor dasatinib due to activation of the YAP pathway. Furthermore, using breast cancer data from the TCGA and a cohort of cancer-derived patient samples, we find that both TPX2 expression and YAP activation are present in a significant percentage of cancer tumor samples, providing poor prognosis, being therefore putative biomarkers for dasatinib therapy.

show abstract

“…Tyrosination was shown to regulate the recruitment of Clip-170 (a microtubule plus-end-tracking protein) to microtubule tips, and in addition, it was reported to recruit the motor protein dynein through its regulator dynactin which interacted directly with the α -tubulin tail [ 49 – 51 ]. SRC kinase-mediated tyrosine phosphorylation of TUBB3 was demonstrated to regulate mitotic spindle dynamics in prostate cancers [ 52 ]. In cancer stem cells, GLUT1, GRP78, VDAC, and Ephrins interacted with β -tubulin isotypes (e.g., βIVb) in maintaining cancer stem cell niches [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Prediction of anti-microtubular target proteins of tubulins and their interacting proteins using Gene Ontology tools

Babu

2023

Journal of Genetic Engineering and Biotechnology

View full text Add to dashboard Cite

Background Tubulins are highly conserved globular proteins involved in stabilization of cellular cytoskeletal microtubules during cell cycle. Different isoforms of tubulins are differentially expressed in various cell types, and their protein–protein interactions (PPIs) analysis will help in identifying the anti-microtubular drug targets for cancer and neurological disorders. Numerous web-based PPIs analysis methods are recently being used, and in this paper, I used Gene Ontology (GO) tools, e.g., Stringbase, ProteomeHD, GeneMANIA, and ShinyGO, to identify anti-microtubular target proteins by selecting strongly interacting proteins of tubulins. Results I used 6 different human tubulin isoforms (two from each of α-, β-, and γ-tubulin) and found several thousands of node-to-node protein interactions (highest 4956 in GeneMANIA) and selected top 10 strongly interacting node-to-node interactions with highest score, which included 7 tubulin family protein and 6 non-tubulin family proteins (total 13). Functional enrichment analysis indicated a significant role of these 13 proteins in nucleation, polymerization or depolymerization of microtubules, membrane tethering and docking, dorsal root ganglion development, mitotic cycle, and cytoskeletal organization. I found γ-tubulins (TUBG1, TUBGCP4, and TUBBGCP6) were known to contribute majorly for tubulin-associated functions followed by α-tubulin (TUBA1A) and β-tubulins (TUBB AND TUBB3). In PPI results, I found several non-tubular proteins interacting with tubulins, and six of them (HTT, DPYSL2, SKI, UNC5C, NINL, and DDX41) were found closely associated with their functions. Conclusions Increasing number of regulatory proteins and subpopulation of tubulin proteins are being reported with poor understanding in their association with microtubule assembly and disassembly. The functional enrichment analysis of tubulin isoforms using recent GO tools resulted in identification of γ-tubulins playing a key role in microtubule functions and observed non-tubulin family of proteins HTT, DPYSL2, SKI, UNC5C, NINL, and DDX41 strongly interacting functional proteins of tubulins. The present study yields a promising model system using GO tools to narrow down tubulin-associated proteins as a drug target in cancer, Alzheimer’s, neurological disorders, etc.

show abstract

SRC Kinase-Mediated Tyrosine Phosphorylation of TUBB3 Regulates Its Stability and Mitotic Spindle Dynamics in Prostate Cancer Cells

Cited by 8 publications

References 50 publications

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling

Prediction of anti-microtubular target proteins of tubulins and their interacting proteins using Gene Ontology tools

Contact Info

Product

Resources

About