Growth signals typically come in the form
of chemical agonists outside of cells that bind to protein receptors on
cells. Activated receptors are responsible for transmitting the signal
to the inside of the cell, ultimately generating a growth messenger
Researchers from the University of Wisconsin School of Medicine and
Public Health and Carbone Cancer Center have better defined a pro-growth
signaling pathway common to many cancers that, when blocked, kills
cancer cells but leaves healthy cells comparatively unharmed. The
study, published in the journal Nature Cell Biology
establish new avenues of therapeutic treatments for many types of solid
‘Proteins known to be in the cancer signal transmission cascade are present on endosomes inside the cell, supporting the idea that the key growth message is being signaled from these internal compartments.’
Two years ago, research out of UW-Madison Professor Richard
Anderson's lab found that some of these agonist-stimulated
receptors continue to transmit the signal even after they have
been pulled into the cell, sequestered in vesicles called
endosomes and presumably on their way to being degraded.
to dogma in the literature, receptors shouldn't make PIP3 at
these internal sites, but they were," Anderson says. "We set out to
ask, 'Why is that?'"
In this new study, a postdoctoral fellow in
Anderson's lab, Suyong Choi, showed that the proteins known to be in
this signal transmission cascade were all present on endosomes inside
the cell, supporting the idea that the key growth message was being
signaled from these internal compartments.
However, there was one fact
which they could not biologically explain: In a typical signaling
cascade, each step amplifies the signal, suggesting there should be more
and more of the messenger molecules; but here, levels of PIP3 and other
intermediary messengers were too low to be detected in endosomes.
scaffold completely solves this issue, because it acts like an assembly
line, bringing together all of the proteins and passing one messenger
molecule to the next protein in the cascade until the last protein,
PI3K, is activated and generates PIP3," Anderson says.
"Suyong Choi found that the scaffolding protein IQGAP1 brings all
of these proteins together like a happy family on the endosome. It's an
incredibly efficient mechanism."
Choi discovered that the IQGAP1
complex pulls together all of the signaling components in
the PI3K pathway. Remarkably, this assembly happens in response to
nearly all agonists that switch on growth and cell survival signals in
cells. Once Choi had established how the proteins in the complex
interacted, he was able to block scaffold formation in cells by adding a
small, competing fragment of the IQGAP1 protein.
beautifully to block assembly of IQGAP1 and PI3K complex," Anderson
says. "The really cool thing was, when we treated different cells with
these inhibitory fragments, the disruption of IQGAP1 and PI3K complex
formation had almost no effect on normal cells but it killed cancer
cells very efficiently."
PI3K is an essential protein, and cells
(and whole organisms) die if they do not have any functional
PI3K because the protein is involved in multiple signaling pathways.
However, it is specifically this pathway, mediated through IQGAP1, that is required for the growth and survival of cancer cells but
not normal cells. In fact, mice lacking IQGAP1 develop normally but are
resistant to developing solid tumors.
have developed PI3K inhibitors, but many of these have failed, likely
because they're hitting all PI3Ks and the different pathways," Anderson
said. "If you can specifically disrupt this agonist-activated PI3K
pathway, the one that has a specific role in cancer, then you
can effectively treat cancers. We think that's what this study is
The researchers further showed that this same
scaffolding was used to transmit insulin signaling, suggesting the
pathway may play a role in the onset of diabetes and cardiovascular
diseases as well as cancers.