Abstract
Integrin, an αβ heterodimeric cell surface receptor for the extracellular matrix (ECM), carries two tyrosine phosphorylation motifs in the cytoplasmic tail of the β subunit. NPXY (Asn-Pro-x-Tyr) is a conserved tyrosine phosphorylation motif that binds to the phospho-tyrosine binding (PTB) domain. We generated a tyrosine to glutamic acid (E) mutation to modify tyrosine (Y) into a negatively charged amino NPXY in the βpat-3 integrin of Caenorhabditis elegans. The transgenic rescue animal displayed defects in gonad migration and tail morphology. Also, the mutant animals produced a high number of males, suggesting that the Y to E mutation in βpat-3 integrin causes a phenotype similar to that of Him mutant. Further analyses revealed that males of pat-3(Y804E) and him-4/hemicentin share additional phenotypes such as abnormal gonad and unsuccessful mating. A pat-3 transgenic rescue mutant with a non-polar phenylalanine (F) in NPXY, pat-3(Y792/804F), suppressed the high male number, defective mating, inviable zygote, and the abnormal gonad of him-4 mutants, indicating that Y to F mutation in both NPXY motifs suppressed the him-4 phenotypes. This finding supports the idea that the ECM determines the activation state in integrin NPXY motifs; him-4/hemicentin may directly or indirectly interact with integrins and maintain the NPXY non-charged. Our findings provide new insight into a suppressive role of an ECM molecule in integrin NPXY phosphorylation.
Highlights
Integrin is a cell surface receptor for the extracellular matrix (ECM), playing a significant role in cell adhesion and tissue organization
Integrin is an excellent molecule to study the function of the NPXY motif, because two NPXY motifs are conserved in many species and arranged in the cytoplasmic tail of β integrins (Calderwood et al, 2002, 2003; Calderwood, 2004) (Figure 1B)
When the pat-3(Y804E) males were examined for mating, we found no signs of mating success (Table 1 and see section “Materials and Methods”)
Summary
Integrin is a cell surface receptor for the extracellular matrix (ECM), playing a significant role in cell adhesion and tissue organization. The β integrin cytoplasmic tail contains conserved tyrosine phosphorylation sites These are NPXY (tyrosine phosphorylation) motifs essential for recruitment of focal adhesion proteins such as talin (Oxley et al, 2008) and kindlins (Larjava et al, 2008; Moser et al, 2009; Plow et al, 2009). Our genetic analysis revealed that the nonpolar replacement mutant, pat-3(Y792/804F), suppressed Him, abnormal gonad, and unsuccessful mating of him-4/hemicentin mutants, suggesting that HIM-4/hemicentin interacts with pat integrin and modulates the charged state of the NPXY This suggests that NPXY motifs in β integrin play a vital role in its function, which impacts many aspects of development and interaction between cells and their surroundings
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