ACTIVATION OF JAR3, BUT NOT JAK1, IS CRITICAL TO INTERLEUKIN-4 (IL4) STIMULATED PROLIFERATION AND REQUIRES A MEMBRANE-PROXIMAL REGION OF IL4 RECEPTOR-ALPHA
Mg. Malabarba et al., ACTIVATION OF JAR3, BUT NOT JAK1, IS CRITICAL TO INTERLEUKIN-4 (IL4) STIMULATED PROLIFERATION AND REQUIRES A MEMBRANE-PROXIMAL REGION OF IL4 RECEPTOR-ALPHA, The Journal of biological chemistry, 270(16), 1995, pp. 9630-9637
The tyrosine kinases JAK1 and JARS have been shown to undergo tyrosine
phosphorylation in response to interleukin-2 (IL), IL4, IL7, and IL9,
cytokines which share the common IL2 receptor gamma-chain (IL2R gamma
), and evidence has been found for a preferential coupling of JAK3 to
IL2R gamma and JAK1 to IL2R beta. Here we show, using human premyeloid
TF-1 cells, that IL4 stimulates JAK3 to a larger extent than JAK1, ba
sed upon three different evaluation criteria. These include a more vig
orous tyrosine phosphorylation of JAK3 as measured by anti-phosphotyro
sine immunoblotting, a more marked activation of JAK3 as determined by
in vitro tyrosine kinase assays and a more manifest presence of JAK3
in activated IL4-receptor complexes. These observations suggest that I
L4 receptor signal transduction does not depend on equimolar heterodim
erization of JAK1 and JAK3 following IL4-induced heterodimerization of
IL4R alpha and IL2R gamma. Indeed, when human IL4R alpha was stably e
xpressed in mouse BA/F3 cells, robust IL4-induced proliferation and JA
K3 activation occurred without detectable involvement of JAK1, JAK2, o
r TYK2. The present study suggests that JAK1 plays a subordinate role
in IL4 receptor signaling, and that in certain cells exclusive JARS ac
tivation may mediate IL4-induced cell growth. Moreover, mutational ana
lysis of human IL4R alpha showed that a membrane-proximal cytoplasmic
region was critical for JARS activation, while the I4R motif was not,
which is compatible with a role of JARS upstream of the recruitment of
the insulin receptor substrate-1/4PS signaling proteins by IL4 recept
ors.