Serpico, Angela Flavia (2021) Mitotic spindle assembly relies on localized control of Cdk1 activity. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Mitotic spindle assembly relies on localized control of Cdk1 activity |
| Autori: | Autore Email Serpico, Angela Flavia angelaflavia.serpico@unina.it |
| Data: | 12 Luglio 2021 |
| Numero di pagine: | 79 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 33 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Grieco, Domenico [non definito] |
| Data: | 12 Luglio 2021 |
| Numero di pagine: | 79 |
| Parole chiave: | mitotic spindle; Cdk1; Wee1 |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare Area 05 - Scienze biologiche > BIO/12 - Biochimica clinica e biologia molecolare clinica Area 05 - Scienze biologiche > BIO/13 - Biologia applicata Area 06 - Scienze mediche > MED/04 - Patologia generale |
| Depositato il: | 19 Lug 2021 10:57 |
| Ultima modifica: | 07 Giu 2023 10:41 |
| URI: | http://www.fedoa.unina.it/id/eprint/13700 |
Abstract
During cell division, mitosis involves profound rearrangements of the cytoskeleton such that the interphase microtubular network is rapidly dismantled while highly dynamic microtubules (MTs) nucleated from centrosomes start a chromosome search and capture process to build up the mitotic spindle, the structure deputed to chromosome segregation. The wholesale MT reorganization at mitotic entry is triggered by the activation of cyclin B/cyclin-dependent kinase 1 (cdk1) complex (Cdk1). During interphase, Cdk1 is kept inactive by Wee1-like protein kinase (Wee1)- and membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (Myt1)-dependent inhibitory phosphorylation while, at mitosis onset, Cdk1 gets activated via dephosphorylation at these sites by cell division cycle 25 phosphatase (Cdc25) and starts positive feedback loops that ensure its full activation. Active Cdk1 drives dissolution of the long interphase MT arrays by phosphorylating and inhibiting stabilizing microtubule associated proteins (MAPs), like microtubule associated protein 4 (Map4) and colonic and hepatic tumor overexpressed gene (ch-Tog). Nevertheless, most of these MAPs are required for spindle MT growth. How mitotic spindles assemble overcoming the highly MT destabilizing environment imposed by active Cdk1 is unknown. During this work we uncovered that a small fraction of Cdk1, exclusively localized at spindle structures, avoided Cdc25 activating action and persisted in a phosphorylated and inhibited form (i-Cdk1). Abating i-Cdk1 impaired spindle assembly while its restoration rescued normal spindle formation. We found that centrosomes and their nucleating MTs promoted i-Cdk1 formation by tightly binding Wee1 but not Cdc25. Moreover, i-Cdk1 was required to locally promote serine/threonine protein phosphatase 1 (PP1)-dependent reversal of inhibitory phosphorylation of stabilizing MAPs for spindle MT growth. Thus, these data highlight a new control element for spindle assembly relying on compartmentalized control of Cdk1 activity.
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