„Kadherin-1” változatai közötti eltérés

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A lap 2024. január 8., 15:03-kori változata

Nem tévesztendő össze a következővel: CDH1 ADC/C-aktivátorfehérje.
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Kadherin-1
Azonosítók
JelCDH1
Entrez999
OMIM192090
RefSeqNM_004360
UniProtP12830
PDB2O72
Egyéb adatok
Lokusz16. krom. q22.1

A kadherin-1, más néven epitél (E-) kadherin a CDH1 gén által kódolt fehérje.[1] Mutációi összefüggnek a gyomor-, a mell-, a colorectalis, a pajzsmirigy- és a petefészekrákkal. Nevezik még CD324-nek (differenciációs csoport 324). Tumorszupresszorgén.[2][3]

Történet

A kadherin sejtközi adhéziós fehérjéket Takeicsi Maszatosi fedezte fel, aki 1966-ban kezdett dolgozni adherens epitél sejtekkel.[4] Munkáját csirkeembriók lencsedifferenciációjának vizsgálatával kezdte a Nagojai Egyetemen, ahol a retinasejtek lencserostdifferenciáció-szabályzását vizsgálta. Ehhez kezdetben korábban tenyésztett retinaidegsejteket tartalmazó közegeket gyűjtött, és szuszpenzióba helyezte szemlencsék epitél sejtjeit. Megfigyelte, hogy e közegben később kötődnek a sejtek, mint a hagyományosban. Ezután más környezetekben, például fehérje, magnézium és kalcium jelenlétében is vizsgálta a sejteket. Ekkor még kevéssé volt ezen ionok szerepe ismert.[5] Így Takeicsi mnkája a kalcium sejtközi adhézióban való szerepének felfedezésében jelentős volt.[6][7]

Takeicsi több kadherint fedezett fel, az első az E-kadherin. F9-sejtekkel immunizált patkányokat használva az Okada laboratórium hallgatójával, Szuzuki Noboruval működött együtt ECCD1 egérantitestek létrehozásában. Ez akadályozta a sejtadhéziót, és kalciumdependens kölcsönhatást mutatott antigénjével, az E-kadherinnel.[8] Antitesteloszlások vizsgálatával felfedezték, hogy számos epitél sejttel reagál ez.[9] Az E-kadherin felfedezésében észlelt késés oka feltehetően a sejtadhézió vizsgálatához használt modell volt. A hörcsög-V79-sejtek nem E-kadherint, hanem 20 később felfedezett altípust expresszáltak.[10]

Function

A kadherin-1 a kadherinek szupercsaládjának klasszikus tagja. Az általa kódolt fehérje kalciumdependens sejtközi adhéziós glikoprotein, mely 5 sejten kívüli kadherinismétlődésből, egy transzmembrán régióból és egy erősen állandósult citoplazmatikus farokból áll. Mutációi összefüggnek gyomor-, mell-, colorectalis, pajzsmirigy- és petefészekrákokkal. A funkcióvesztés feltehetően közrejátszik a rák előrehaladásában a proliferáció, invázió és a metasztázis növekedésével. A fehérje ektodoménje a bakteriális adhéziót mediálja az emlőssejtekhez, a citoplazmatikus domén az internalizációhoz szükséges. Az azonosított transzkriptumváltozatokat a konszenzussplicinghely mutációja okozza.[11]

Az E-kadherin a legjobban tanulmányozott kadherin, fontos transzmembrán fehérje az adherens kapcsolatokban. Az adherens kapcsolatok az E-kadherin mellett p120-kateninből, β-kateninből és α-kateninből állnak.[12] Together, these proteins stabilize epithelial tissues and regulate intercellular exchange. The structure of E-cadherin consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and a highly-phosphorylated intracellular domain. This region is vital to beta-catenin binding and, therefore, to E-cadherin function.[13] Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.

E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction.[14] Cell–cell interactions mediated by E-cadherin are crucial to blastula formation in many animals.[15]

Neighboring epithelial cells can transduce mechanical information via E-cadherin interactions, here depicted as a generic cadherin, Actin filaments are associated with several adherens complex proteins, such as α-catenin and vinculin. The activity of these proteins and E-cadherin allows for tensile stimulus to be exerted one from actomyosin system to another, permitting tissue coordination.

Sejtciklus

E-cadherin has been known to mediate adhesion-dependent proliferation inhibition by triggering cell cycle exit via contact inhibition of proliferation (CIP) and recruitment of the Hippo pathway.[16] E-cadherin adhesions inhibit growth signals, which initiates a kinase cascade that excludes the transcription factor YAP from the nucleus. Conversely, decreasing cell density (decreasing cell-cell adhesion) or applying mechanical stretch to place E-cadherins under increased tension promotes cell cycle entry and YAP nuclear localization.[17]

Sejtrendezés epitél csírázás során

E-cadherin has been found to have a role in epithelial morphogenesis and branching, such as during the formation of epithelial buds. Physiologically, branching is an important feature that allows tissues, such as salivary glands and pancreatic buds, to maximize functional surface areas.[18] It has been discovered that the application of appropriate growth factors and extracellular matrix can induce branching in tissue, but the mechanisms of branching appear to differ between single-layered and stratified epithelium.[19][20]

Single-layered branching occurs as nearby mechanical influences, such as airway smooth muscle cells, cause epithelial sheets buckle.[21] Stratified epithelial cannot respond to stimulus in the same way due to the absence of internal space (i.e. lumen) that allows tissue sheet flexibility.[22] Instead, it appears stratified epithelial buds are generated by the clefting of one original epithelial cell cluster. Investigations in salivary glands revealed that buds expand as new cells are uniformly distributed across the peripheral surface. Surface-derived cells continue to replicate and produce daughter cells, which then move from the interior back to the surface. This movement is maintained by an E-cadherin gradient, in which surface cells have low levels of E-cadherin and interior cells have high levels of E-cadherin. Such a system allows for increased interactions between interior cells, limiting mobility and ensuring they remain more static, while likewise ensuring the surface cells are comparatively less hindered. This gives a fluidity to their movement within the stratified epithelia, until they begin to accumulate at the edges of the forming bud.[23]

While this gradient is important for cell sorting within the tissue layers, additional experiments show that the physical generation of buds is dependent on cell-matrix interactions[13]. As low-E-cadherin cells accumulate at the surface, they tightly adhere to the basement membrane, allowing the epithelia to cleft and bud as the surface area expands and folds. If the structure of the basement membrane is disrupted, such as by collagenase, the low-E-cadherin cells no longer have a barrier to interact with. Surface-derived daughter cells fail to remain at the periphery to initiate budding under these conditions, yet budding can be reestablished with basement membrane restoration.

Sejtrendezés gastrulatio során

The adhesive qualities of E-cadherin indicate it could be a relevant player within germ-layer organization during gastrulation. Gastrulation is a fundamental phase of vertebrate development in which three primary germ layers are defined, ectoderm, mesoderm, and endoderm.[24] Cell adhesion has been linked to progenitor sorting, where ectoderm was found to be the least cohesive and mesoderm was comparable to endoderm cohesion.[25] Initial work depleting calcium from media and, more strikingly, the impairment of E-cadherin both greatly impaired primary germ layer cohesion. As cohesive properties of progenitors were further examined, higher concentrations of CDH-1 were found on mesoderm or endoderm than on ectoderm. While adhesion is a factor in gastrulation, the driving factor in cell sorting was instead found to be in cell-cortex tension[15]. Disrupting the actomyosin-dependent cell cortex with actin depolymerizers and myosin-II inhibitors interrupted impeded tension balances and was sufficient to inhibit cell sorting. This is likely because cell sorting is driven by energy minimization. WIthin tissue energetics, tension plays an important role in ensuring: (1) lower surface tension surrounds the higher surface tension germ layers; (2) aggregate surface tension is appropriately increased; and (3) tension is higher at the cell-to-medium interface than cell-to-cell interface[8]. Cellular adhesion must still be considered for a complete understanding of progenitor sorting, as it directly  diminishes the energetic effects of tension. Combined, tension and adhesion increase aggregate surface tension, which allows for unique interactions between differing germ layers and appropriate cell sorting.[26]

Sejtvándorlás

Cell migration is vital for constructing and maintaining multicellular organization. Morphogenesis involves numerous events of cell migration, such as the migration of epithelial sheets in gastrulation, the neural crest cell migration, or posterior lateral line primordium migration.[27] It is known that cells that begin to internalize at the dorsal surface of the embryo mobilize to extend the axis and direct posterior prechordal plate and notochord precursors. How cells are able to orient themselves during this process is dependent on the protrusions of “follower cells” to guide the leading cells in the appropriate direction.[28]

E-cadherin has an active role in collective cell dynamics, such as by directing the migration of mesendoderm towards the animal pole.[29] It has been demonstrated that the genetic knockdown of E-cadherin results in random orientations of the cellular protrusions, resulting in cellular migration that is random and no longer unified.[30] Knockdowns in leading and following cell groups both resulted in a loss of orientation, which could be rescued by re-expressing E-cadherin. The information E-cadherin transmitted from cell to cell was directional information inherent to cytoskeletal tension. Restoring only the external adhesion capability of E-cadherin was not enough to rescue protrusion orientation during knockdown experiments. The intracellular domain of E-cadherin is essential due to its mechanotransduction characteristics; it interacts with alpha-catenin and vinculin and altogether allows for the mechanosensation of tension.[31][32][33] The exact mechanism on how mechanosensation directs actin-rich protrusions is yet to be elucidated, however initial investigations suggest regulation of PI3K activity is involved.[34]

E-kadherin általi erőátvitel

Adherens junctions (AJs) form homotypic dimers between neighboring cells, where the intracellular protein complex interacts with the actomyosin cytoskeleton. p120-catenin controls E-cadherin membrane localization, while β-catenin and α-catenin provide the link that connect AJs to the cytoskeleton. If AJs experience tensile force when β-catenin is bound, the interaction, known as a catch bond interaction, between α-catenin and F-actin is reinforced. This exposes the a previously inaccessible actin binding site within α-catenin.[35] The binding of vinculin to α-catenin offers the protein complex another linkage with actin in addition to recruiting proteins such as Mena/VASP.[36]

Coordination of the actomyosin network between neighboring cells permits collective cellular activity, such as contractility during morphogenesis. This network is better equipped to maintain tissue integrity if under intercellular stress, but should not be considered a static system. E-cadherin is involved in cellular responses and transcriptional activators that impact migration, growth, and reorganization.[37][38]

Hatásmechanizmus

E-cadherin interacts with its environment through numerous pathways. One mechanism that it is involved in is the migration of tissue sheets via cryptic lamellipodia. Rac1 and its effectors act at the front edge of this structure to initiate actin polymerization, allowing the cell to generate force at the cellular margin and forward movement.[39] As leader cells extend their lamellipodia, followers also extend protrusions to collect information on where the tissue sheet it moving. Cell migration is dependent on the generation of a polarized state, with Rac1 at the front and Rho-mediated adhesion at the rear. The release of Merlin from cell contacts partially mediates concomitant migration by acting as a mechanochemical transducer.[40] This tumour suppressor protein relocalizes from cortical cell-cell junctions to the cytoplasm during migration to coordinate Rac1 activation. Other pathways can then modulate Merlin activity, such as circumferential actin belts, which suppresses the nuclear export of Merlin and its interaction with E-cadherin.[41]

Kölcsönhatások

A CDH1 az alábbi fehérjékkel kölcsönhat:

Sablon:Div col end

Klinikai jelentőség

Immunohistochemistry for E-cadherin in invasive lobular carcinoma, showing loss of expression in invasive tumor cells (white arrow).

Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis.[59][60] E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.[60] E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry.[61] E-cadherin and N-cadherin temporal-spatial expression are tightly regulated during cranial suture fusion in craniofacial development.[62]

Rák

Áttét

Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.[63]

EMT

E-cadherin is a crucial type of cell–cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT.[63]

MET

The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell–cell adhesions again and return to an epithelial state.[63]

Példák

  • Az öröklött CDH1-inaktiváló mutációk összefüggnek az örökletes diffúz gyomorrákkal. E mutáció esetén a diffúz gyomorrák kockázata 70%, a CDH1-mutációs nők esetén a lobularis mellráké 60%.[64]
  • A CDH1 inaktivációja a vad típusú allél elvesztésével együtt a lobularis mellrákok 56%-ában.[65][66]
  • A CDH1 inaktivációja a diffúz gyomorrákok 50%-ában.[67]
  • Az E-kadherin-expresszió teljes elvesztése a lobularis mellrákok 84%-ában.[68]

Genetikai és epigenetikai irányítás

Egyes fehérjék, például a SNAI1,[69][70] a ZEB2,[71] a SNAI2[72][73] TWIST1[74] és a ZEB1[75] csökkentik az E-kadherin-expressziót. E transzkripciós faktorok megváltozásakor az E-kadherin transzkripciós represszorai túlexpresszálódnak a tumorsejtekben. Egy másik géncsoport, például az AML1, a p300 és a HNF3[76] növelheti az E-kadherin-expressziót.[77]

Az E-kadherin epigenetikai tanulmányozásához M. Lombaerts et al. genomszintű expressziós tanulmányt végeztek 23 humán emlősejtvonalon. Eredményeik két fibroblaszt-, illetve epitél fenotípusú fő csoportot mutattak ki. A fibroblaszt-fenotípusú csoportok CDH-1-promotere részben vagy teljesen metilálódott, míg az epitél fenotípusúaké vad típusú és mutáns CDH1-gyel rendelkezik. Megfigyelték továbbá, hogy az EMT a CDH1-promoter hipermetilációjával történhet mellráksejtekben, de a CDH1 mutációs inaktivációjában nem történhet EMT. Ez ellentmond annak a hipotézisnek, mely szerint az E-kadherin elvesztése az EMT kezdeti vagy elsődleges oka. Tehát „az E-kadherin-transzkripciós inaktiváció következmény, egy teljes program része sokkal súlyosabb hatásokkal, mint az E-kadherin-expresszió elvesztése önmagában”.[77]

Más tanulmányok szerint az E-kadherin-expresszió epigenetikus szabályzása történik metasztáziskor. Az E-kadherin 5’-CpG-sziget metilációs mintái nem stabilak. Sok epitél tumor áttétjének előrehaladásakor időleges E-kadherin-csökkenés történik, és a heterogén E-kadherin-vesztés a heterogén E-kadherin-promoter-minta miatt jelenik meg.[78]

Jegyzetek

  1. ↑ Huntsman DG, Caldas C (1999. március 1.). „Assignment1 of the E-cadherin gene (CDH1) to chromosome 16q22.1 by radiation hybrid mapping”. Cytogenetics and Cell Genetics 83 (1–2), 82–83. o. DOI:10.1159/000015134. PMID 9925936.  
  2. ↑ Semb H, Christofori G (1998. december 1.). „The tumor-suppressor function of E-cadherin”. American Journal of Human Genetics 63 (6), 1588–1593. o. DOI:10.1086/302173. PMID 9837810.  
  3. ↑ Wong AS, Gumbiner BM (2003. június 1.). „Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin”. The Journal of Cell Biology 161 (6), 1191–1203. o. DOI:10.1083/jcb.200212033. PMID 12810698.  
  4. ↑ Takeichi M (2018. január 1.). „Historical review of the discovery of cadherin, in memory of Tokindo Okada”. Development, Growth & Differentiation 60 (1), 3–13. o. DOI:10.1111/dgd.12416. PMID 29278270.  
  5. ↑ Takeichi M, Ozaki HS, Tokunaga K, Okada TS (1979. május 1.). „Experimental manipulation of cell surface to affect cellular recognition mechanisms”. Developmental Biology 70 (1), 195–205. o. DOI:10.1016/0012-1606(79)90016-2. PMID 456740.  
  6. ↑ Urushihara H, Ozaki HS, Takeichi M (1979. május 1.). „Immunological detection of cell surface components related with aggregation of Chinese hamster and chick embryonic cells”. Developmental Biology 70 (1), 206–216. o. DOI:10.1016/0012-1606(79)90017-4. PMID 110634.  
  7. ↑ Urushihara H, Takeichi M (1980. június 1.). „Cell-cell adhesion molecule: identification of a glycoprotein relevant to the Ca2+-independent aggregation of Chinese hamster fibroblasts”. Cell 20 (2), 363–371. o. DOI:10.1016/0092-8674(80)90622-4. PMID 7388946.  
  8. ↑ Yoshida-Noro C, Suzuki N, Takeichi M (1984. január 1.). „Molecular nature of the calcium-dependent cell-cell adhesion system in mouse teratocarcinoma and embryonic cells studied with a monoclonal antibody”. Developmental Biology 101 (1), 19–27. o. DOI:10.1016/0012-1606(84)90112-X. PMID 6692973.  
  9. ↑ Lampugnani MG, Resnati M, Raiteri M, Pigott R, Pisacane A, Houen G, Ruco LP, Dejana E (1992. szeptember 1.). „A novel endothelial-specific membrane protein is a marker of cell-cell contacts”. The Journal of Cell Biology 118 (6), 1511–1522. o. DOI:10.1083/jcb.118.6.1511. PMID 1522121.  
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  11. ↑ Entrez Gene: CDH1 cadherin 1, type 1, E-cadherin (epithelial)
  12. ↑ Hartsock A, Nelson WJ (2008. március 1.). „Adherens and tight junctions: structure, function and connections to the actin cytoskeleton”. Biochimica et Biophysica Acta (BBA) - Biomembranes 1778 (3), 660–669. o. DOI:10.1016/j.bbamem.2007.07.012. PMID 17854762.  
  13. ↑ Faux MC, Coates JL, Kershaw NJ, Layton MJ, Burgess AW (2010. november 1.). „Independent interactions of phosphorylated β-catenin with E-cadherin at cell-cell contacts and APC at cell protrusions”. PLOS ONE 5 (11), e14127. o. DOI:10.1371/journal.pone.0014127. PMID 21152425.  
  14. ↑ Hyafil F, Babinet C, Jacob F (1981). „Cell-cell interactions in early embryogenesis: a molecular approach to the role of calcium”. Cell 26 (3 Pt 1), 447–454. o. DOI:10.1016/0092-8674(81)90214-2. PMID 6976838.  
  15. ↑ Fleming TP, Papenbrock T, Fesenko I, Hausen P, Sheth B (2000. augusztus 1.). „Assembly of tight junctions during early vertebrate development”. Seminars in Cell & Developmental Biology 11 (4), 291–299. o. DOI:10.1006/scdb.2000.0179. PMID 10966863.  
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  17. ↑ Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD (2011. március 1.). „Yap1 acts downstream of α-catenin to control epidermal proliferation” (english nyelven). Cell 144 (5), 782–795. o. DOI:10.1016/j.cell.2011.02.031. PMID 21376238.  
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  19. ↑ Nogawa H, Ito T (1995. április 1.). „Branching morphogenesis of embryonic mouse lung epithelium in mesenchyme-free culture”. Development 121 (4), 1015–1022. o. DOI:10.1242/dev.121.4.1015. PMID 7538066.  
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  21. ↑ Kim HY, Pang MF, Varner VD, Kojima L, Miller E, Radisky DC, Nelson CM (2015. szeptember 1.). „Localized Smooth Muscle Differentiation Is Essential for Epithelial Bifurcation during Branching Morphogenesis of the Mammalian Lung”. Developmental Cell 34 (6), 719–726. o. DOI:10.1016/j.devcel.2015.08.012. PMID 26387457.  
  22. ↑ Nelson CM (2016. február 1.). „On Buckling Morphogenesis”. Journal of Biomechanical Engineering 138 (2), 021005. o. DOI:10.1115/1.4032128. PMID 26632268.  
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  24. ↑ Shimizu T, Yabe T, Muraoka O, Yonemura S, Aramaki S, Hatta K, Bae YK, Nojima H, Hibi M (2005. június 1.). „E-cadherin is required for gastrulation cell movements in zebrafish”. Mechanisms of Development 122 (6), 747–763. o. DOI:10.1016/j.mod.2005.03.008. PMID 15905076.  
  25. ↑ Krieg M, Arboleda-Estudillo Y, Puech PH, Käfer J, Graner F, Müller DJ, Heisenberg CP (2008. április 1.). „Tensile forces govern germ-layer organization in zebrafish”. Nature Cell Biology 10 (4), 429–436. o. DOI:10.1038/ncb1705. PMID 18364700.  
  26. ↑ Lecuit T, Lenne PF (2007. augusztus 1.). „Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis”. Nature Reviews. Molecular Cell Biology 8 (8), 633–644. o. DOI:10.1038/nrm2222. PMID 17643125.  
  27. ↑ Olson HM, Nechiporuk AV (2018. május 31.). „Using Zebrafish to Study Collective Cell Migration in Development and Disease”. Frontiers in Cell and Developmental Biology 6, 83. o. DOI:10.3389/fcell.2018.00083. PMID 30175096.  
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  30. ↑ Dumortier JG, Martin S, Meyer D, Rosa FM, David NB (2012. október 1.). „Collective mesendoderm migration relies on an intrinsic directionality signal transmitted through cell contacts”. Proceedings of the National Academy of Sciences of the United States of America 109 (42), 16945–16950. o. DOI:10.1073/pnas.1205870109. PMID 23027928.  
  31. ↑ Grashoff C, Hoffman BD, Brenner MD, Zhou R, Parsons M, Yang MT, McLean MA, Sligar SG, Chen CS, Ha T, Schwartz MA (2010. július 1.). „Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics”. Nature 466 (7303), 263–266. o. DOI:10.1038/nature09198. PMID 20613844.  
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