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PAK1

PAK1
PAK1
Protein PAK1 PDB 1e0a.png
사용 가능한 구조물
PDB직교 검색: PDBe RCSB
식별자
별칭PAK1, PAKalpha, p21(RAC1) 활성화 키나제 1, IDDMSD
외부 IDOMIM: 602590 MGI: 1339975 호몰로진: 1936 GeneCard: PAK1
직교체
종인간마우스
엔트레스

5058

18479

앙상블

ENSG00000149269

ENSMUSG00000030774

유니프로트

Q13153

O88643

RefSeq(mRNA)

NM_001128620
NM_002576

NM_011035
NM_001357362
NM_001357363
NM_001357364
NM_001357365

RefSeq(단백질)

n/a

위치(UCSC)Cr 11: 77.32 – 77.47MbCr 7: 97.44 – 97.56Mb
PubMed 검색[3][4]
위키다타
인간 보기/편집마우스 보기/편집

세린/스레오닌-단백질 키나아제 PAK 1은 인간에서 PAK1 유전자에 의해 인코딩되는 효소다.[5][6]

PAK1은 그룹 I(PAK1, PAK2 및 PAK3)와 그룹 II(PAK4, PAK6, PAK5/7)로 크게 구분되는 세린/트레오닌 키나제스의 6개 PAK 계열 중 하나이다.[7][8]PAK는 진화적으로 보존되어 있다.[9]PAK1은 세포질과 핵에서 구별되는 하위 세포영역에서 국소화한다.[10]PAK1은 시토스켈레톤 리모델링, 표현파 신호, 유전자 발현을 조절하며 방향 운동성, 침공, 전이, 성장, 세포 주기 진행, 혈관신생 등 다양한 세포 과정에 영향을 미친다.[10][11]PAK1-서명 의존 세포 기능은 PAK1이 인간 암에서 광범위하게 과도하게 압박되고 과다 자극되기 때문에 암을 포함한 생리학적 과정과 질병 과정을 모두 조절한다.[10][12][13]

디스커버리

PAK1은 1994년 맨저와 동료들에 의해 쥐의 뇌에서 Ro GTPases의 이펙터로 처음 발견되었다.[7]인간 PAK1은 중성미자의 세포질 분율에서 Rac1이나 Cdc42의 GTP 의존적 상호작용 파트너로 확인되었으며, 보완 DNA는 1995년 마틴과 동료에 의해 인간 태반 도서관에서 복제되었다.[8]

함수

PAK 단백질은 Rho 계열의 GTPases(Rho GTPases)와 Cytoskeleton 재구성과 핵신호를 연결하는 임계효과의 물질이다.세린/트레오닌 p21 활성화 키나제 계열인 PAK 단백질에는 PAK1, PAK2, PAK3, PAK4가 포함된다.이 단백질들은 작은 GTP 결합 단백질인 Cdc42와 Rac의 표적 역할을 하며 광범위한 생물학적 활동에 관여해왔다.PAK1은 세포 운동성과 형태학을 조절한다.이 유전자의 대체 성분은 발견되었지만, 그들의 전신 성질은 결정되지 않았다.[14]

PAK1 활동의 자극은 생물체계에 기초하는 일련의 세포 과정을 수반한다.결절 신호 분자인 PAK1은 업스트림 활성제뿐 아니라 세포 표면의 단백질에 의해 촉발된 다수의 신호의 수렴 스테이션에 작용하며, 구체적인 표현형으로 해석된다.생화학적 수준에서 이러한 활동은 PAK1의 이펙터가 상호작용하는 기판을 인산화하는 능력에 의해 조절되며, 이는 세포 표현형 응답으로 축적되는 일련의 생화학적 사건을 차례로 설정한다.또한, PAK1 작용은 비계 활동에도 영향을 받는다.PAK1 조절 세포 공정의 예로는 액틴과 미세관섬유, 세포주기 진행 중 중요한 단계, 운동성과 침입, 복스와 에너지 대사, 세포 생존, 혈관신생, DNA-수리, 호르몬 민감성, 유전자 발현 등이 있다.PAK1 신호의 기능적 함의는 종양 발생,[9] 바이러스성 병원체 발생,[15][16] 심혈관계 장애 [17]및 신경 장애에서의 역할에 의해 예시된다.[18]

유전자와 스플라이스 변형

인간 PAK1 유전자는 길이가 153kb이며 23 exon, 5'-UTR의 경우 6 exon, 단백질 코딩(Gene from review)의 경우 17 exon으로 구성된다.6개의 엑손의 대체 스플라이싱은 308-bp에서 3.7-kb 길이까지 20개의 대본을 생성하지만, 12개의 분할된 대본만이 판독 프레임을 개방하고 있으며 10개의 단백질과 2개의 폴리펩타이드 코드를 기록할 것으로 예측된다.나머지 8개 대본 범위는 길이 308-bp에서 863-bp까지 코딩되지 않는 긴 RNA에 대한 것이다.인간 PAK1과는 달리 뮤린 PAK1 유전자는 508-bp에서 3.0-kb 길이까지의 단백질 코드 3개, 비코딩 RNA의 경우 약 900-bp의 2개 등 5개의 대본을 생성한다.

단백질 도메인

PAK 계열의 핵심 도메인은 C-터미널 영역의 키나세 도메인, p21 바인딩 도메인(PBD), 그룹 I PAK의 자동 수신 도메인(AID)을 포함한다.그룹 I PAKs는 한 분자의 AID가 다른 분자의 키나제 영역에 결합되고 GTPase 의존성과 독립적인 방식 모두에서 활성화되는 비활성화된 폐쇄 호모디머 순응으로 존재한다.[13]

활성화/금지

PAK1은 키나제 영역의 촉매 활동을 억제하는 자동 억제 도메인을 포함한다.PAK1 활성제는 이러한 자동 인시브레이션을 완화하고 키나제 활성화로 이어지는 순응적 재배열 및 자동 인산화 이벤트를 개시한다.

IPA-3 (1,1′-disulfanedieldinaphalen-2-ol)는 PAK1의 작은 분자 알로스테릭 억제제다.사전 활성화된 PAK1은 IPA-3에 내성이 있다.활선 셀에서의 억제는 PDGF 자극 ERK 활성화에서 PAK의 중요한 역할을 지원한다.[19]IPA-3를 PAK1 규제 영역으로 되돌릴 수 있는 공밸런트 바인딩은 GTPase 도킹을 방지하고 이후 촉매 활성 상태로 전환하는 것을 방지한다.[20]

전립선암 세포의 PAK1 녹다운은 운동성 감소, MMP9 분비량 감소, TGFβ 발현 증가와 관련이 있는데, 이 경우 성장 억제제다.그러나 IPA-3의 약동학적 특성과 세포 내 바람직하지 않은 리독스 효과는 황하이드리 모이티(sulfhydryl moiety)의 지속적인 감소로 인해 임상 발달에 부적합하다.[20]

업스트림 액티베이터

PAK1 활동 상부 활성기 체인에서는 및 신호의 큰 숫자 EGF,[21]에서 이르기까지 heregulin-beta 1,[22]VEGF,[23]기본 phosphoinositides,[28]fibroblast 성장 factor,[24]혈소판 유래 성장 factor,[25]estrogen,[26]lysophosphatidic acid,[27]ETK,[29]AKT,[30]JAK2,[31일]ERK,[32]카세인 인산화 효소 II,[33]Rac3,[34]인체 자극이 된다.(C-X-C motif)리간드 1,[35]유방 암anti-estrogen 사건.istance 3,[36] Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor,[37] ARG-binding protein 2γ,[38] hepatitis B virus X protein,[39] STE20-related kinase adaptor protein α,[40] RhoI,[41] Klotho,[42] N-acetylglucosaminyl transferase V,[43] B-Raf proto-oncogene,[44] casein kinase 2-interacting protein 1,[45] and filamin A.[46]

다운스트림 이펙터 대상

PAK1의 기능은 다운스트림 이펙터 기판을 인지하는 능력, 비계 활동, 구별되는 아세포 세포 하위 영역으로의 재분배, 직간접적으로 또는 이 모든 메커니즘에 의해 조절된다.암세포의 대표적인 PAK1 이펙터 기판은 다음과 같다.전사 5a-S779,[52]C말단 결합 단백질의 Stathmin-S16,[47]Merlin-S518,[48]Vimentin-S25-S38-S50-S65-S72,[49]히스톤 H3-S10,[50]FilaminA-S2152,[46]에스트로겐 receptor-alpha-S305,[51]신호 변환기와 활성기 1-S158,[53]Raf1-S338,[54]Arpc1b-T21,[55]DLC1-S88,[56]1-T466,[57]SMART/HDAC1-associated을 억누르다 phosphoglucomutase.아니면 Tubulin Cofactor B-S65- protein-S3486-T3568,[58].S128,[59]Snail-S246 혈관 endothelial-cadherin-S665,[61]poly(RC)결합 단백질 1-T60-S246,[62]integrin-linked 인산화 효소 1-T173-S246,[63]epithelium-specific Ets전사 인자 1-S207,[64]ErbB3 결합 단백질 1-T261,[65]핵 receptor-interacting 인자 3-S28,[66]SRC3-delta4-T56-S659-676,[67]beta-catenin-S675,[68]BAD-S111, -LSB- 69[60].]BAD-S112, S136,[70]MEK1-S298,[71][72]CRKII-S41,[73]MORC.CW형 아연 핑거 2-S739,[74][75] 팍실린-S258,[15] 팍실린-S273 패밀리.[76]

게놈 목표물

PAK1 및/또는 PAK1 종속 신호는 혈관 내피 성장 인자,[23] Cyclin D1, [77]인포프락토키나제-근육 이소형,[78] 활성 T세포의 핵 인자,[78] Cyclin B1,[79] 조직 인자 및 조직 인자 경로 억제제,[9][80] Metricoprotinase 9 [81]및 섬유ectin을 포함하여 게놈 표적의 표현을 변조한다.[82]

상호작용

PAK1은 다음과 상호 작용하는 것으로 나타났다.

메모들

참조

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