Recap of Insulin Signaling As A Growth Factor - Online Tutor, Practice Problems & Exam Prep

Insulin, a 51 amino acid peptide hormone, binds to the insulin receptor, a receptor Tyrosine Kinase (RTK), triggering autophosphorylation and activating insulin receptor substrate 1 (IRS 1). This activation leads to a cascade involving adapter protein Grb2, which binds to IRS 1, activating Ras through guanine exchange factor (GEF) Sauce. Ras activates RAF1, which phosphorylates MEK, subsequently activating ERK. ERK enters the nucleus to regulate transcription factors for cell growth. Phosphatases and GTPase-activating proteins (GAPs) help terminate the signal by removing phosphate groups and hydrolyzing GTP, respectively.

Recap of Insulin Signaling As A Growth Factor

Alright. So in this video, we're going to do a recap or a review of insulin signaling as a growth factor. And so really there's nothing new that we're going to cover in this video that we haven't already covered in our previous lesson videos. And so if you're already feeling really good about insulin signaling as a growth factor, then feel free to skip this entire video if you'd like because again, it's not going to cover anything new that we haven't already covered in our previous lesson videos. However, if you're struggling with this even just a little bit, then stick around because a recap or a review could potentially be really helpful for you guys.

Alright. So if we take a look at our large image down below, notice that it's pretty much recapping everything that we covered in our previous lesson videos regarding insulin signaling as a growth factor. And so if we start at the top left up here, of course, we know that the 51 amino acid residue peptide hormone, insulin, is going to act as the ligand here in this situation and bind to the insulin receptor, which we know is an RTK or a receptor tyrosine kinase. And so when insulin binds to the receptor tyrosine kinase here, the insulin receptor, it's going to cause the autophosphorylation of the insulin receptor here and that is going to fully activate the insulin receptor so that it can phosphorylate its substrate, the insulin receptor substrate 1 or IRS1.

And so we have the phosphorylation or the activation of IRS1 here. And of course IRS1 is going to be phosphorylated on tyrosine residue since the tyrosine kinase domains phosphorylate tyrosine residues. And so next, what we have is another adapter protein called GRB2 is going to bind to IRS1 using its SH2 domain. Then, the SH3 domain of GRB2 is going to bind to the guanine exchange factor called SOS or the GEF called SOS. And because it is a GEF, a guanine exchange factor, it's going to assist RAS in exchanging its GDP with high energy GTP.

And so SOS is going to help activate RAS, and RAS will then activate a MAPKK called RAF1. RAF1 will then activate another MAPKK called MEK, phosphorylating it to become active. And then, MEK is a MAPKK that will phosphorylate the MAPK ERK, activating ERK. And then, of course, ERK will make its way into the nucleus so that it can regulate transcription factors that are involved in cell growth.

And so, what you'll notice is that these red arrows that you see here are really just representing the removal of phosphate groups. And so, here you can see that the removal of phosphate groups is going to be occurring via the action of phosphatases, and this helps to terminate the signal. And notice that this arrow right here, is showing the GTP hydrolysis activity of RAS, which we know is really slow and can really only occur under the help of GAP proteins, which are GTPase activating proteins. And so the GAP proteins will help accelerate the inactivation of RAS to help terminate the signal.

And so, recall from our previous lesson videos that we actually introduced this crazy story to help you guys memorize the most important components of this insulin signaling as a growth factor in the correct order. And so recall that the story started off with IRS1 activation. And so the Internal Revenue Services is going to give a tax refund where the cell can get this cash and use the cash to order 2 orders of Grubhub. And then, of course, when the food arrives, the cell adds hot sauce to the food, and that hot sauce ends up activating a rash. And so the cell calls Dr. Raph, and Dr. Raph says, you know what? I'm going to make the arcing pain go away. And so, hopefully, that will help you with the insulin signaling as a growth factor. And so really this here concludes our recap or our review of insulin signaling as a growth factor. And as we move forward, we'll be able to get a little bit more practice. So I'll see you guys in our next video.

How is Ras activity turned off?

• A. It is turned off by phosphorylation.
• B. It is turned off by hydrolysis of its bound GTP to GDP.
• C. It is turned off by hydrolysis of its bound GDP to GTP.
• D. It is turned off by hydrolysis of its bound GTP to GMP.

In a tumor cell line, Raf-1 is mutated such that it is constitutively activated by Ras even in the absence of insulin signaling. How can you inhibit the growth of this tumor cell line?

• A. Blocking insulin receptor autophosphorylation.
• B. Inhibiting the kinase activity of ERK.
• C. Preventing the production of cAMP.
• D. Blocking the recruitment of PI3K to the plasma membrane by IRS-1.

Here’s what students ask on this topic:

What is the role of insulin in cell growth signaling?

Insulin, a 51 amino acid peptide hormone, plays a crucial role in cell growth signaling by binding to the insulin receptor, a receptor Tyrosine Kinase (RTK). This binding triggers autophosphorylation of the receptor, leading to the activation of insulin receptor substrate 1 (IRS 1). The activated IRS 1 initiates a cascade involving adapter proteins and kinases, ultimately activating ERK, which enters the nucleus to regulate transcription factors involved in cell growth. This pathway ensures that cells grow and proliferate in response to insulin.

How does the insulin receptor get activated?

The insulin receptor, a receptor Tyrosine Kinase (RTK), gets activated when insulin binds to it. This binding causes autophosphorylation of the receptor on specific tyrosine residues. The autophosphorylation fully activates the receptor, enabling it to phosphorylate its substrate, insulin receptor substrate 1 (IRS 1). This phosphorylation event is crucial for the downstream signaling cascade that leads to various cellular responses, including growth and metabolism regulation.

What is the function of IRS 1 in insulin signaling?

Insulin receptor substrate 1 (IRS 1) functions as a key mediator in insulin signaling. Once the insulin receptor is activated through autophosphorylation, it phosphorylates IRS 1 on tyrosine residues. This phosphorylation creates docking sites for other signaling proteins, such as Grb2, which further propagate the signal downstream. IRS 1 activation leads to a cascade of events involving Ras, RAF1, MEK, and ERK, ultimately resulting in the regulation of transcription factors that control cell growth and metabolism.

How is the insulin signaling pathway terminated?

The insulin signaling pathway is terminated through the action of phosphatases and GTPase-activating proteins (GAPs). Phosphatases remove phosphate groups from proteins in the signaling cascade, effectively deactivating them. GAPs accelerate the hydrolysis of GTP to GDP on Ras, inactivating Ras and halting the downstream signaling. These mechanisms ensure that the signal is transient and tightly regulated, preventing prolonged or inappropriate activation of the pathway.

What is the role of ERK in insulin signaling?

ERK (Extracellular signal-Regulated Kinase) plays a pivotal role in insulin signaling by acting as the final kinase in the MAPK (Mitogen-Activated Protein Kinase) cascade. Once activated by MEK, ERK translocates into the nucleus, where it phosphorylates various transcription factors. These transcription factors then regulate the expression of genes involved in cell growth, proliferation, and survival. ERK's activity ensures that the cellular response to insulin is properly executed, promoting growth and metabolic functions.