Pennino, Francesco Paolo
(2020)
The metastasis suppressor protein NM23-H1 interacts with PI3K catalytic subunit p110α and impairs PI3K-Akt axis.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
The metastasis suppressor protein NM23-H1 interacts with PI3K catalytic subunit p110α and impairs PI3K-Akt axis |
| Autori: |
| Autore | Email |
|---|
| Pennino, Francesco Paolo | francescopaolo.pennino@unina.it |
|
| Data: |
12 Marzo 2020 |
| Numero di pagine: |
77 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: |
Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: |
32 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Avvedimento, Vittorio Enrico | avvedim@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Zollo, Massimo | [non definito] |
|
| Data: |
12 Marzo 2020 |
| Numero di pagine: |
77 |
| Parole chiave: |
NM23H1-PI3K-METASTASIS |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/03 - Genetica medica |
[error in script]
[error in script]
| Depositato il: |
25 Mar 2020 10:39 |
| Ultima modifica: |
08 Nov 2021 12:13 |
| URI: |
http://www.fedoa.unina.it/id/eprint/13149 |
Abstract
This thesis documents a novel interaction between the catalytic subunit of PI3K class I subunit alpha p110α (PI3KCA) and the anti-metastatic protein NM23-H1 (NDPKA) and analyzes the functional consequences of this interaction. A yeast two hybrid screening of a cDNA library derived from an immortalized lymphoblastoid cell line (LCL) using NM23-H1 as “bait”, identified the PI3K Class I catalytic subunit p110α (PI3KCA) as a strong binding partner. The interaction was validated by GST pull down and two-way co-immunoprecipitation experiments.
Among the various components that regulate PI3K signalling, class I p110α is associated with neoplastic progression because it is frequently mutated or overexpressed in different types of tumors. NM23-H1 is a well characterized protein with different enzymatic activities (nucleoside diphosphate kinase, protein histidine kinase, serine/threonine protein kinase, 3'-5' exonuclease) and with metastasis suppressor activity in different tumors. Loss of function NM23-H1 mutants, which determine the Killer of Prune phenotype in Drosophila, abrogate completely the anti-metastatic activity and do not interact with PI3K p110α. HEK293T, MDA-MB435 and MDA-MB231 cell lines stably expressing NM23H1 inhibit Akt phosphorylation induced by the Epidermal growth factor (EGF). Under the same conditions NM23-H1 protein mutants fail to inhibit EGF-induced AKT phosphorylation. NM23H1 knockdown in HEK293T cell lines stimulates Akt phosphorylation. The main functional consequence of NM23 and p110α interaction is the inhibition of cell motility and clonogenic potential. In fact, in MDA-MB435 cells expressing p110α, wild type NM23H1, not the mutants, counteracts the enhancement of motility, invasion, adhesion, and the formation of filopodia (cell motility structures) induced by expression of p110α.
These results provide a new mechanism that explains the NM23-H1anti-metastatic properties during cancer progression and pave the way to a novel translational perspective.
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