P21-Activated Kinase 4 Pak4 Maintains Embryonic Stem Cell Pluripotency via Akt Activation
Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specifi...
Saved in:
| Published in: | Stem cells (Dayton, Ohio) Vol. 40; no. 10; p. 892 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
21.10.2022
|
| ISSN: | 1549-4918, 1549-4918 |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specific signaling networks. Here, we reveal the involvement of the p21-activated kinase 4 (Pak4), a serine/threonine kinase, in sustaining murine ESC (mESC) pluripotency. Pak4 is highly expressed in R1 ESC cells compared with embryonic fibroblast cells and its expression is progressively decreased during differentiation. Manipulations using knockdown and overexpression demonstrated a positive relationship between Pak4 expression and the clonogenic potential of mESCs. Moreover, ectopic Pak4 expression increases reprogramming efficiency of Oct4-Klf4-Sox2-Myc-induced pluripotent stem cells (iPSCs) whereas Pak4-knockdown iPSCs were largely incapable of generating teratomas containing mesodermal, ectodermal and endodermal tissues, indicative of a failure in differentiation. We further establish that Pak4 expression in mESCs is transcriptionally driven by the core pluripotency factor Nanog which recognizes specific binding motifs in the Pak4 proximal promoter region. In turn, the increased levels of Pak4 in mESCs fundamentally act as an upstream activator of the Akt pathway. Pak4 directly binds to and phosphorylates Akt at Ser473 with the resulting Akt activation shown to attenuate downstream GSK3β signaling. Thus, our findings indicate that the Nanog-Pak4-Akt signaling axis is essential for maintaining mESC self-renewal potential with further importance shown during somatic cell reprogramming where Pak4 appears indispensable for multi-lineage specification.Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specific signaling networks. Here, we reveal the involvement of the p21-activated kinase 4 (Pak4), a serine/threonine kinase, in sustaining murine ESC (mESC) pluripotency. Pak4 is highly expressed in R1 ESC cells compared with embryonic fibroblast cells and its expression is progressively decreased during differentiation. Manipulations using knockdown and overexpression demonstrated a positive relationship between Pak4 expression and the clonogenic potential of mESCs. Moreover, ectopic Pak4 expression increases reprogramming efficiency of Oct4-Klf4-Sox2-Myc-induced pluripotent stem cells (iPSCs) whereas Pak4-knockdown iPSCs were largely incapable of generating teratomas containing mesodermal, ectodermal and endodermal tissues, indicative of a failure in differentiation. We further establish that Pak4 expression in mESCs is transcriptionally driven by the core pluripotency factor Nanog which recognizes specific binding motifs in the Pak4 proximal promoter region. In turn, the increased levels of Pak4 in mESCs fundamentally act as an upstream activator of the Akt pathway. Pak4 directly binds to and phosphorylates Akt at Ser473 with the resulting Akt activation shown to attenuate downstream GSK3β signaling. Thus, our findings indicate that the Nanog-Pak4-Akt signaling axis is essential for maintaining mESC self-renewal potential with further importance shown during somatic cell reprogramming where Pak4 appears indispensable for multi-lineage specification. |
|---|---|
| AbstractList | Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specific signaling networks. Here, we reveal the involvement of the p21-activated kinase 4 (Pak4), a serine/threonine kinase, in sustaining murine ESC (mESC) pluripotency. Pak4 is highly expressed in R1 ESC cells compared with embryonic fibroblast cells and its expression is progressively decreased during differentiation. Manipulations using knockdown and overexpression demonstrated a positive relationship between Pak4 expression and the clonogenic potential of mESCs. Moreover, ectopic Pak4 expression increases reprogramming efficiency of Oct4-Klf4-Sox2-Myc-induced pluripotent stem cells (iPSCs) whereas Pak4-knockdown iPSCs were largely incapable of generating teratomas containing mesodermal, ectodermal and endodermal tissues, indicative of a failure in differentiation. We further establish that Pak4 expression in mESCs is transcriptionally driven by the core pluripotency factor Nanog which recognizes specific binding motifs in the Pak4 proximal promoter region. In turn, the increased levels of Pak4 in mESCs fundamentally act as an upstream activator of the Akt pathway. Pak4 directly binds to and phosphorylates Akt at Ser473 with the resulting Akt activation shown to attenuate downstream GSK3β signaling. Thus, our findings indicate that the Nanog-Pak4-Akt signaling axis is essential for maintaining mESC self-renewal potential with further importance shown during somatic cell reprogramming where Pak4 appears indispensable for multi-lineage specification.Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation into specialized cell lineages requires intricate control governed by both intrinsic and extrinsic factors along with the actions of specific signaling networks. Here, we reveal the involvement of the p21-activated kinase 4 (Pak4), a serine/threonine kinase, in sustaining murine ESC (mESC) pluripotency. Pak4 is highly expressed in R1 ESC cells compared with embryonic fibroblast cells and its expression is progressively decreased during differentiation. Manipulations using knockdown and overexpression demonstrated a positive relationship between Pak4 expression and the clonogenic potential of mESCs. Moreover, ectopic Pak4 expression increases reprogramming efficiency of Oct4-Klf4-Sox2-Myc-induced pluripotent stem cells (iPSCs) whereas Pak4-knockdown iPSCs were largely incapable of generating teratomas containing mesodermal, ectodermal and endodermal tissues, indicative of a failure in differentiation. We further establish that Pak4 expression in mESCs is transcriptionally driven by the core pluripotency factor Nanog which recognizes specific binding motifs in the Pak4 proximal promoter region. In turn, the increased levels of Pak4 in mESCs fundamentally act as an upstream activator of the Akt pathway. Pak4 directly binds to and phosphorylates Akt at Ser473 with the resulting Akt activation shown to attenuate downstream GSK3β signaling. Thus, our findings indicate that the Nanog-Pak4-Akt signaling axis is essential for maintaining mESC self-renewal potential with further importance shown during somatic cell reprogramming where Pak4 appears indispensable for multi-lineage specification. |
| Author | Thorne, Rick Francis Liu, Lianxin Zhang, Yuwei Wu, Mian Li, Mingyue Cheng, Fangyuan Liu, Guangzhi |
| Author_xml | – sequence: 1 givenname: Fangyuan surname: Cheng fullname: Cheng, Fangyuan – sequence: 2 givenname: Mingyue surname: Li fullname: Li, Mingyue – sequence: 3 givenname: Rick Francis surname: Thorne fullname: Thorne, Rick Francis – sequence: 4 givenname: Guangzhi surname: Liu fullname: Liu, Guangzhi – sequence: 5 givenname: Yuwei surname: Zhang fullname: Zhang, Yuwei – sequence: 6 givenname: Mian surname: Wu fullname: Wu, Mian – sequence: 7 givenname: Lianxin surname: Liu fullname: Liu, Lianxin |
| BookMark | eNpNjj1PwzAURS1UJNrCyuyRJfT5I048RlGhiCIiAQNT5TivkmnilNqp6L8nEh0Yrs6djs6MTHzvkZBbBvcMtFiE2Nk2LMKPsZDCBZmyVOpEapZP_v0rMgvhC4DJNM-n5LPiLClsdEcTsaHPzpuAVNLK7CR9Mc7HcYEuu_pw6r2z9C1iR0tsW1q1w8Ht-4jenujRGVrsIj2rXO-vyeXWtAFvzpyTj4fle7lK1q-PT2WxTqxULCYiU2ghlzkKlakxkDNtBGsYKlEraxVvJKCV9VagBJ5aoZVA0DU0jCmT8jm5-_PuD_33gCFuOhfsGGg89kPYcKUVQMZ1yn8BH3dXmA |
| CitedBy_id | crossref_primary_10_1038_s41417_024_00748_w crossref_primary_10_1016_j_ebiom_2024_105162 |
| ContentType | Journal Article |
| Copyright | The Author(s) 2022. Published by Oxford University Press. |
| Copyright_xml | – notice: The Author(s) 2022. Published by Oxford University Press. |
| DBID | 7X8 |
| DOI | 10.1093/stmcls/sxac050 |
| DatabaseName | MEDLINE - Academic |
| DatabaseTitle | MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Biology |
| EISSN | 1549-4918 |
| GroupedDBID | --- 05W 0R~ 123 18M 1OB 2WC 3WU 4.4 53G 5RE 5WD 7X8 8-0 8-1 AABZA AACZT AAESR AAONW AAPXW AARHZ AAUAY AAVAP AAZKR ABCUV ABDFA ABEJV ABGNP ABHFT ABJNI ABLJU ABMNT ABNHQ ABPTD ABVGC ABXVV ABXZS ACGFO ACGFS ACIWK ACPOU ACPRK ACUFI ACUTJ ADBBV ADGKP ADIPN ADKYN ADQBN ADVEK ADXAS ADZMN AENEX AFBPY AFFZL AFGWE AFRAH AFZJQ AHGBF AHMBA AHMMS AJBYB AJEEA AJNCP ALMA_UNASSIGNED_HOLDINGS ALXQX AMYDB ATGXG AZBYB AZVAB BAWUL BCRHZ BEYMZ BMXJE BRXPI CS3 DCZOG DIK DU5 E3Z EMOBN F5P FD6 G-S GX1 H13 HHY HZ~ IH2 KOP KSI KSN LATKE LEEKS LITHE LMP LOXES LUTES LYRES MY~ N9A NNB NOMLY NTU O9- OBOKY OCZFY OIG OJZSN OK1 OPAEJ OVD OWPYF P2P P2W PQQKQ RAO ROX SUPJJ TEORI TR2 WBKPD WIN WOHZO WOQ XV2 ZZTAW ~S- |
| ID | FETCH-LOGICAL-c461t-376ec0848e3676918219a31d1e63b6cc62d40ec4bf3e4025c3963e09b0d116a52 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 2 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000834287800001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1549-4918 |
| IngestDate | Sun Sep 28 04:23:40 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 10 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c461t-376ec0848e3676918219a31d1e63b6cc62d40ec4bf3e4025c3963e09b0d116a52 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | https://academic.oup.com/stmcls/article-pdf/40/10/892/46589992/sxac050.pdf |
| PQID | 2696007295 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2696007295 |
| PublicationCentury | 2000 |
| PublicationDate | 2022-10-21 |
| PublicationDateYYYYMMDD | 2022-10-21 |
| PublicationDate_xml | – month: 10 year: 2022 text: 2022-10-21 day: 21 |
| PublicationDecade | 2020 |
| PublicationTitle | Stem cells (Dayton, Ohio) |
| PublicationYear | 2022 |
| SSID | ssj0014588 |
| Score | 2.4183478 |
| Snippet | Exploiting the pluripotent properties of embryonic stem cells (ESCs) holds great promise for regenerative medicine. Nevertheless, directing ESC differentiation... |
| SourceID | proquest |
| SourceType | Aggregation Database |
| StartPage | 892 |
| Title | P21-Activated Kinase 4 Pak4 Maintains Embryonic Stem Cell Pluripotency via Akt Activation |
| URI | https://www.proquest.com/docview/2696007295 |
| Volume | 40 |
| WOSCitedRecordID | wos000834287800001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LS8NAEF7UKnjxLb5ZwevS7GbzOkkpFUEtBRXqqexONhBME23SYv-9s2lqD14Ej4EQlpmdb77M7nxDyA3-I2M4i4QJw0Mm8ZEp7XEWYOqJInCNDOpG4ceg3w-Hw2jQFNzK5lrlEhNroI4LsDXytvAjv5a59m4_PpmdGmVPV5sRGuuk5SKVsVe6guHqFMF2YdZ6qdJOUuPhj2ij2y6rMWRlu_xS4HjOLyCus8vd7n_XtUd2Gl5JO4uNsE_WTH5AthaTJueH5G0gOOtAPcvMxPQhzTF7UUmRQEr6pNLcVghK2hvrydyK5dLnyoxp12QZHWRTBJbCcus5naWKdt4r2nwKnXpEXu96L9171kxVYCB9XllEMWBV9I0Va0OrIGYpl8fc-K72AXwRS8eA1Ak6ChkRuBijxom0E3PuK08ck428yM0JoUg9NBLOMARM8iLQykRuEoaxhkQHCUSn5HppsxHuWnsUoXJTTMvRympnf3jnnGwL23WAKUPwC9JKMDLNJdmEWZWWk6va6d9_27Yk |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=P21-Activated+Kinase+4+Pak4+Maintains+Embryonic+Stem+Cell+Pluripotency+via+Akt+Activation&rft.jtitle=Stem+cells+%28Dayton%2C+Ohio%29&rft.au=Cheng%2C+Fangyuan&rft.au=Li%2C+Mingyue&rft.au=Thorne%2C+Rick+Francis&rft.au=Liu%2C+Guangzhi&rft.date=2022-10-21&rft.issn=1549-4918&rft.eissn=1549-4918&rft.volume=40&rft.issue=10&rft.spage=892&rft_id=info:doi/10.1093%2Fstmcls%2Fsxac050&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1549-4918&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1549-4918&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1549-4918&client=summon |