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CD99 inhibits CD98-mediated β1 integrin signaling through SHP2-mediated FAK dephosphorylation

Kyoung Jin Lee1, Yeon Ho Yoo1, Min Seo Kim1

  • 1Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.

Experimental Cell Research
|July 15, 2015
PubMed

Insights

CD99 and CD98 oppositely regulate cell adhesion by modulating focal adhesion kinase (FAK) signaling. CD98 promotes adhesion, while CD99 inhibits it through distinct molecular mechanisms involving SHP2 phosphatase.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • CD99 and CD98 are transmembrane glycoproteins known to oppositely regulate β1 integrin signaling.
  • The precise molecular mechanisms underlying this inverse regulation remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which CD99 and CD98 oppositely regulate β1 integrin signaling.
  • To investigate the role of focal adhesion kinase (FAK) and associated protein complexes in this process.

Main Methods:

  • Antibody-mediated crosslinking of CD99 and CD98 proteins.
  • Analysis of FAK phosphorylation at Y397.
  • Investigation of protein complex formation (PKCα-syntenin-FAK, IPP-Akt1-syntenin).
  • Assessment of Src homology region 2 domain-containing phosphatase-2 (SHP2) recruitment and activity.
  • Evaluation of FAK-talin and talin-β1 integrin interactions.
  • Measurement of cell-extracellular matrix (ECM) adhesion.

Main Results:

  • CD98 crosslinking induced FAK phosphorylation and promoted the formation of PKCα-syntenin-FAK and IPP-Akt1-syntenin complexes, enhancing β1 integrin signaling.
  • CD99 crosslinking disrupted these complexes via FAK dephosphorylation, mediated by SHP2 recruitment and activation.
  • SHP2 activation by CD99 led to the disruption of FAK-talin and talin-β1 integrin interactions, reducing cell-ECM adhesion.

Conclusions:

  • This study reveals the molecular mechanisms of CD99 and CD98's opposing regulation of β1 integrin signaling.
  • CD99 inhibits cell adhesion by activating SHP2, leading to FAK dephosphorylation and disruption of key adhesion complexes.
  • These findings offer potential therapeutic targets for inflammation and cancer treatment.
Keywords:
CD98CD99Cell–ECM adhesionFAKInflammation and cancerSHP2β1 integrin

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