Ca2+/Calmodulin Dependent Protein Kinase Kinase-2 (CaMKK2) promotes Protein Kinase G (PKG)-dependent actin cytoskeletal assembly to increase tumor metastasis Article Swipe
Debarati Mukherjee
,
Rebecca A. Previs
,
Corinne Haines
,
Muthana Al Abo
,
Patrick K. Juras
,
Kyle C. Strickland
,
Binita Chakraborty
,
Sandeep Artham
,
Regina S. Whitaker
,
Katherine Hebert
,
Jake Fontenot
,
Steven R. Patierno
,
Jennifer A. Freedman
,
Frank H. Lau
,
Matthew E. Burow
,
Ching‐yi Chang
,
Donald P. McDonnell
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.04.17.536051
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.04.17.536051
Triple-negative breast cancers (TNBCs) tend to become highly invasive early during cancer development. Despite some successes in the initial treatment of patients diagnosed with early-stage localized TNBC, the rate of metastatic recurrence remains high with poor long-term survival outcomes. Here we show that elevated expression of the serine/threonine-kinase, Calcium/Calmodulin (CaM)-dependent protein kinase kinase-2 (CaMKK2), is highly correlated with tumor invasiveness. We determined that genetic disruption of CaMKK2 expression, or inhibition of its activity, disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor-prognosis ovarian cancer subtype, shares many genetic features with TNBC, and importantly, CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Probing the mechanistic links between CaMKK2 and metastasis we defined the elements of a new signaling pathway that impacts actin cytoskeletal dynamics in a manner which increases cell migration/invasion and metastasis. Notably, CaMKK2 increases the expression of the phosphodiesterase PDE1A which decreases the cGMP-dependent activity of protein kinase G1 (PKG1). This inhibition of PKG1 results in decreased phosphorylation of Vasodilator-Stimulated Phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate contraction/cell movement. Together, these data establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis. Further, it credentials CaMKK2 as a therapeutic target that can be exploited in the discovery of agents for use in the neoadjuvant/adjuvant setting to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.04.17.536051
- https://www.biorxiv.org/content/biorxiv/early/2023/04/18/2023.04.17.536051.full.pdf
- OA Status
- green
- Cited By
- 1
- References
- 100
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4366332247
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4366332247Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2023.04.17.536051Digital Object Identifier
- Title
-
Ca2+/Calmodulin Dependent Protein Kinase Kinase-2 (CaMKK2) promotes Protein Kinase G (PKG)-dependent actin cytoskeletal assembly to increase tumor metastasisWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-04-18Full publication date if available
- Authors
-
Debarati Mukherjee, Rebecca A. Previs, Corinne Haines, Muthana Al Abo, Patrick K. Juras, Kyle C. Strickland, Binita Chakraborty, Sandeep Artham, Regina S. Whitaker, Katherine Hebert, Jake Fontenot, Steven R. Patierno, Jennifer A. Freedman, Frank H. Lau, Matthew E. Burow, Ching‐yi Chang, Donald P. McDonnellList of authors in order
- Landing page
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https://doi.org/10.1101/2023.04.17.536051Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2023/04/18/2023.04.17.536051.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2023/04/18/2023.04.17.536051.full.pdfDirect OA link when available
- Concepts
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Cancer research, Biology, Protein kinase A, Kinase, Metastasis, Cell migration, Cell biology, Cancer, Cell, Biochemistry, GeneticsTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2023: 1Per-year citation counts (last 5 years)
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100Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.results | 174 |
| abstract_inverted_index.setting | 235 |
| abstract_inverted_index.(HGSOC), | 91 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Further, | 213 |
| abstract_inverted_index.Notably, | 151 |
| abstract_inverted_index.activity | 164 |
| abstract_inverted_index.assembly | 192 |
| abstract_inverted_index.controls | 207 |
| abstract_inverted_index.disease. | 119 |
| abstract_inverted_index.dynamics | 141 |
| abstract_inverted_index.elements | 131 |
| abstract_inverted_index.elevated | 44 |
| abstract_inverted_index.features | 101 |
| abstract_inverted_index.invasive | 9 |
| abstract_inverted_index.kinase-2 | 53 |
| abstract_inverted_index.motility | 210 |
| abstract_inverted_index.patients | 22, 241 |
| abstract_inverted_index.restrict | 237 |
| abstract_inverted_index.subtype, | 97 |
| abstract_inverted_index.survival | 38 |
| abstract_inverted_index.(CaMKK2), | 54 |
| abstract_inverted_index.Together, | 197 |
| abstract_inverted_index.activity, | 73 |
| abstract_inverted_index.decreased | 176 |
| abstract_inverted_index.decreases | 161 |
| abstract_inverted_index.diagnosed | 23, 242 |
| abstract_inverted_index.discovery | 227 |
| abstract_inverted_index.disrupted | 74 |
| abstract_inverted_index.establish | 200 |
| abstract_inverted_index.exploited | 224 |
| abstract_inverted_index.increases | 146, 153 |
| abstract_inverted_index.localized | 26, 247 |
| abstract_inverted_index.long-term | 37 |
| abstract_inverted_index.movement. | 196 |
| abstract_inverted_index.outcomes. | 39 |
| abstract_inverted_index.outgrowth | 77 |
| abstract_inverted_index.regulates | 190 |
| abstract_inverted_index.signaling | 135, 204 |
| abstract_inverted_index.successes | 16 |
| abstract_inverted_index.treatment | 20 |
| abstract_inverted_index.validated | 114 |
| abstract_inverted_index.xenograft | 83, 115 |
| abstract_inverted_index.High-grade | 87 |
| abstract_inverted_index.correlated | 57 |
| abstract_inverted_index.determined | 62 |
| abstract_inverted_index.disruption | 65 |
| abstract_inverted_index.expression | 45, 155 |
| abstract_inverted_index.facilitate | 194 |
| abstract_inverted_index.high-risk, | 93 |
| abstract_inverted_index.inhibition | 70, 107, 171 |
| abstract_inverted_index.metastasis | 127 |
| abstract_inverted_index.metastatic | 31, 76, 110 |
| abstract_inverted_index.recurrence | 32 |
| abstract_inverted_index.targetable | 202 |
| abstract_inverted_index.credentials | 215 |
| abstract_inverted_index.early-stage | 25, 244 |
| abstract_inverted_index.effectively | 108 |
| abstract_inverted_index.expression, | 68 |
| abstract_inverted_index.mechanistic | 122 |
| abstract_inverted_index.metastasis. | 150, 212 |
| abstract_inverted_index.progression | 111 |
| abstract_inverted_index.spontaneous | 75 |
| abstract_inverted_index.therapeutic | 219 |
| abstract_inverted_index.cytoskeletal | 140 |
| abstract_inverted_index.development. | 13 |
| abstract_inverted_index.importantly, | 105 |
| abstract_inverted_index.invasiveness | 239 |
| abstract_inverted_index.invasiveness. | 60 |
| abstract_inverted_index.Phosphoprotein | 180 |
| abstract_inverted_index.cGMP-dependent | 163 |
| abstract_inverted_index.poor-prognosis | 94 |
| abstract_inverted_index.(CaM)-dependent | 50 |
| abstract_inverted_index.Triple-negative | 1 |
| abstract_inverted_index.phosphorylation | 177 |
| abstract_inverted_index.contraction/cell | 195 |
| abstract_inverted_index.phosphodiesterase | 158 |
| abstract_inverted_index.Calcium/Calmodulin | 49 |
| abstract_inverted_index.hypophosphorylated | 185 |
| abstract_inverted_index.migration/invasion | 148 |
| abstract_inverted_index.neoadjuvant/adjuvant | 234 |
| abstract_inverted_index.CaMKK2-PDE1A-PKG1-VASP | 203 |
| abstract_inverted_index.Vasodilator-Stimulated | 179 |
| abstract_inverted_index.serine/threonine-kinase, | 48 |
| cited_by_percentile_year.max | 94 |
| cited_by_percentile_year.min | 89 |
| corresponding_author_ids | https://openalex.org/A5062055452 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 17 |
| corresponding_institution_ids | https://openalex.org/I170897317 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/1 |
| sustainable_development_goals[0].score | 0.550000011920929 |
| sustainable_development_goals[0].display_name | No poverty |
| citation_normalized_percentile.value | 0.57390368 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |