BACKGROUND: Scaffold proteins modulate cellular signaling by facilitating 
assembly of specific signaling pathways. However, there is at present little 
information if and how scaffold proteins functionally interact with each other.
RESULTS: Here, we show that two scaffold proteins, caveolin-1 and IQGAP1, are 
required for phosphorylation of the actin associated pool of extracellular 
signal regulated kinase 1 and 2 (ERK1/2) in response to protein kinase C 
activation. We show by immunofluorescence and proximity ligation assays, that 
IQGAP1 tethers ERK1/2 to actin filaments. Moreover, siRNA experiments 
demonstrate that IQGAP1 is required for activation of actin-bound ERK1/2. 
Caveolin-1 is also necessary for phosphorylation of actin-bound ERK1/2 in 
response to protein kinase C, but is dispensible for ERK1/2 association with 
actin. Simultaneous knock down of caveolin-1 and IQGAP1 decreases total phorbol 
ester-induced ERK1/2 phosphorylation to the same degree as single knock down of 
either caveolin-1 or IQGAP1, indicating that caveolin-1 and IQGAP1 operate in 
the same ERK activation pathway. We further show that caveolin-1 knock down, but 
not IQGAP1 knock down, reduces C-Raf phosphorylation in response to phorbol 
ester stimulation.
CONCLUSIONS: Based on our data, we suggest that caveolin-1 and IQGAP1 assemble 
distinct signaling modules, which are then linked in a hierarchical arrangement 
to generate a functional ERK1/2 activation pathway.