The syndecans are a type of cell surface adhesion receptor that initiates 
intracellular signaling events through receptor clustering mediated by their 
highly conserved transmembrane domains (TMDs). However, the exact function of 
the syndecan TMD is not yet fully understood. Here, we investigated the specific 
regulatory role of the syndecan-2 TMD. We found that syndecan-2 mutants in which 
the TMD had been replaced with that of syndecan-4 were defective in 
syndecan-2-mediated functions, suggesting that the TMD of syndecan-2 plays one 
or more specific roles. Interestingly, syndecan-2 has a stronger tendency to 
form sodium dodecyl sulfate (SDS)-resistant homodimers than syndecan-4. Our 
structural studies showed that a unique phenylalanine residue (Phe(167)) enables 
an additional molecular interaction between the TMDs of the syndecan-2 
homodimer. The presence of Phe(167) was correlated with a higher tendency toward 
oligomerization, and its replacement with isoleucine significantly reduced the 
SDS-resistant dimer formation and cellular functions of syndecan-2 (e.g. cell 
migration). Conversely, replacement of isoleucine with phenylalanine at this 
position in the syndecan-4 TMD rescued the defects observed in a mutant 
syndecan-2 harboring the syndecan-4 TMD. Taken together, these data suggest that 
Phe(167) in the TMD of syndecan-2 endows the protein with specific functions. 
Our work offers new insights into the signaling mediated by the TMD of syndecan 
family members.