Downstream Components of the Receptor Tyrosine Kinase Signaling Pathway

Slide 1 · Downstream Components of the

Receptor Tyrosine Kinase

Signaling Pathway

RAS • MAPK • PI3K/AKT • tumor suppressor brakes

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Trace growth factor receptor signals through RAS, MAPK and PI3K/AKT.

Explain normal RAS nucleotide cycling and the protective roles of GAPs, NF1 and PTEN.

Interpret oncogenic alterations in RAS, BRAF and PI3K and their therapeutic implications.

Slide 3 · Growth signals must be transmitted inside the cell

Growth factor

Activated RTK

Cytoplasmic effectors

Nuclear response

Ligand binding activates the receptor; The cytoplasmic tail undergoes tyrosine phosphorylation.

Intracellular adaptors and signal-transducing proteins relay this extracellular instruction.

Cancer can deregulate signaling at any point in this chain.

Slide 4 · An oncogenic lesion can uncouple growth from ligand

Physiologic signaling

Oncogenic signaling

Requires a growth factor input

A downstream mutant may signal without it

Receptor activation is transient

Growth-promoting activity becomes persistent

Controls restrain signal duration

Mutations may disable the restraints

A mutant signaling protein can bypass the need for an activated receptor.

Slide 5 · RAS sits immediately downstream of many RTKs

RTK phosphorylation creates docking sites for downstream signaling complexes.

RAS converts receptor input into intracellular kinase-cascade activation.

RAS is an intracellular signaling node rather than a growth factor receptor.

Activated RTK

RAS

Downstream cascades

Slide 6 · RTK signaling divides into two major effector arms

Activated RTK / RAS

RAF

MAPK cascade

Pro-growth transcription

PI3K

AKT

Growth / survival

The MAPK arm chiefly transmits mitogenic signals to nuclear transcription machinery. • The PI3K/AKT arm coordinates growth, metabolism, protein synthesis and survival.

Slide 7 · Signals move through distinct biochemical switches

Component

Functional mechanism

RTK

Receptor with tyrosine kinase activity

RAS

Small G protein, activated by bound GTP

RAF / AKT

Intracellular serine/threonine kinases

GAP / PTEN

Negative regulators of signaling

The mechanisms differ; All may become targets of cancer-associated alterations.

Slide 8 · Human RAS proteins are encoded by three genes

HRAS, KRAS and NRAS encode closely related RAS proteins.

All function as nucleotide-regulated signal-transducing G proteins.

The shared GDP/GTP switch explains how multiple RAS genes can act as oncogenes.

HRAS

KRAS

NRAS

Three genes, one common signaling logic.

Slide 9 · RAS is membrane-associated, not a transmembrane RTK

Plasma membrane

Membrane-anchored RAS

Kinase effectors

RAS proteins are associated with the plasma membrane.

A membrane anchor helps position RAS near signaling complexes activated by RTKs.

Subcellular localization connects receptor activation to RAS function.

Slide 10 · GDP-bound and GTP-bound RAS are different states

RAS–GDP

INACTIVE

RAS–GTP

ACTIVE

GDP release

GTP binding

RAS–GDP is the relatively inactive state.

RAS–GTP is the active, signal-transmitting state.

GDP/GTP exchange changes RAS conformation and downstream interactions.

Slide 11 · Growth factor stimulation initiates the RAS switch

Growth factor + RTK

RAS–GDP

GDP → GTP exchange

RAS–GTP

Activated RTKs promote exchange of bound GDP for GTP on RAS.

RAS undergoes a conformational change and becomes able to signal to effectors.

A receptor input is translated into an active nucleotide state.

Slide 12 · Activated RAS propagates the growth signal

RAS–GTP

MAPK / PI3K–AKT

Gene and protein programs

Cell growth

GTP-bound RAS triggers downstream signaling pathways.

Its activation is normally brief, linking responses to the period of upstream stimulation.

Signal transduction integrates proliferation with metabolic support.

Slide 13 · Intrinsic GTPase activity turns RAS off

RAS–GTP (ON)

GTP hydrolysis

RAS–GDP (OFF)

RAS can hydrolyze bound GTP to GDP.

Hydrolysis returns RAS toward the inactive state, terminating that cycle of signaling.

GTP hydrolysis is a built-in timer for active RAS.

Slide 14 · GTPase-activating proteins accelerate signal termination

RAS–GTP

GAP-assisted hydrolysis

RAS–GDP

GAPs bind activated RAS and markedly accelerate its GTPase activity.

More than a 1000-fold enhancement of RAS GTP hydrolysis.

GAPs are strong physiological brakes on RAS signaling.

Slide 15 · The normal RAS cycle needs both ON and OFF reactions

RAS–GDP (OFF)

RAS–GTP (ON)

Exchange

RTK input

GTP hydrolysis

GAP assistance

Growth factor signaling promotes GDP-to-GTP exchange.

Intrinsic GTPase activity and GAP action return RAS to the GDP-bound state.

Slide 16 · Oncogenic RAS mutations impair GTP hydrolysis

RAS point mutation

Defective GTP hydrolysis

Persistent RAS–GTP

Cancer-associated point mutations can markedly reduce RAS GTPase activity.

Mutant RAS remains predominantly in its signaling-competent GTP-bound form.

The switch becomes functionally stuck in the ON state.

Slide 17 · Normal and mutant RAS differ in signal duration

Normal RAS

Oncogenic RAS

GDP/GTP cycling responds to receptor input

GTP-bound signaling persists despite regulation

GAP-assisted hydrolysis efficiently terminates signal

Mutation diminishes the normal GTPase OFF mechanism

Time-limited downstream signaling

Sustained pro-growth output

Slide 18 · RAS is an oncogene through gain of function

The altered protein acquires persistent signaling activity.

An activating RAS allele can deliver pro-growth cues without continued RTK activation.

This is a molecular mechanism of growth autonomy in cancer.

Mutant RAS

Persistent kinase signaling

Autonomous proliferation

Slide 19 · RAS mutations are widespread, but not universal

15–20%

Of all human tumors (approx.)

Approximately 15%–20% of all human tumors have activating mutations of a RAS gene.

The overall figure conceals major variation between tumor types.

A mutation frequency is descriptive—not a universal diagnostic test or treatment rule.

Slide 20 · RAS mutation prevalence varies across tumor types

Tumor type

Approximate RAS mutation frequency

Pancreatic adenocarcinoma

90%

Colon, endometrial, thyroid cancers

~50% each

Lung adenocarcinoma

~30%

Myeloid leukemias

~30%

Figures are approximate Robbins textbook estimates, not assay-specific prevalence.

Slide 21 · Pancreatic adenocarcinoma illustrates strong RAS selection

~90%

Pancreatic adenocarcinoma

About 90% of pancreatic adenocarcinomas contain a RAS mutation in the supplied text.

A recurrent growth-signal lesion can become common in a particular tumor lineage.

The statistic concerns mutation prevalence—not drug sensitivity.

Slide 22 · Intermediate frequencies require tumor-specific context

Group

RAS alterations in Robbins

Colon / endometrial / thyroid cancers

Approximately half have RAS mutations

Lung adenocarcinoma / myeloid leukemias

Approximately three in ten

Interpretive caution

Mutation distributions differ by histology and cohort

Do not extrapolate one tumor type’s frequency to every malignancy.

Slide 23 · An RAS lesion can substitute for an oncogenic RTK

RTK activation

RAS activation

MAPK / PI3K outputs

In dominant tumor clones with activating RAS mutations, activating RTK mutations are almost always absent.

The source interprets this pattern as functional substitution by activated RAS.

A downstream oncogenic switch may make upstream activation redundant.

Slide 24 · Lung adenocarcinoma illustrates alternate driver routes

RTK-driven molecular subtype

RAS-driven molecular subtype

Abnormal receptor kinase supplies signaling input

RAS mutation supplies downstream activity

RTK-targeted treatment may be relevant

RAS genotype requires separate targeting strategy

Dominant clone typically lacks activating RAS lesion

Dominant clone typically lacks activating RTK lesion

“Almost always” does not mean absolute mutual exclusivity in every cell or tumor.

Slide 25 · Molecular subtypes matter for drug selection

The position of the oncogenic lesion affects the rationale for targeted therapy.

Inhibition of an upstream receptor may not intercept signaling from autonomous downstream RAS.

Tumor genotype therefore matters more than a generic label of “RTK pathway activation.”

Locate the driver

Identify pathway node

Match therapeutic target

Slide 26 · NF1 encodes the RAS-regulating GAP neurofibromin

NF1 gene

Neurofibromin (GAP)

RAS–GTP → RAS–GDP

Neurofibromin 1 is a GTPase-activating protein encoded by NF1.

It promotes RAS inactivation by augmenting GTP hydrolysis.

NF1 is a negative regulator, not another activating RAS family member.

Slide 27 · NF1 loss removes a brake on wild-type RAS

NF1 loss of function

Reduced GAP restraint

Prolonged RAS output

Disabling NF1 mutations reduce the capacity to turn active RAS off.

Elevated RAS pathway output can result even without an oncogenic RAS coding mutation.

A lost brake can phenocopy an activated accelerator.

Slide 28 · Neurofibromatosis type 1 links a syndrome to signaling

Inherited NF1 loss is associated with familial neurofibromatosis type 1.

The clinical syndrome exemplifies predisposition through defective RAS regulation.

The pathogenic principle is loss of a tumor suppressor that normally restricts signaling.

Inherited NF1 defect

Impaired RAS restraint

Tumor predisposition

Slide 29 · RAS activation and NF1 loss have different genetics

RAS activating mutation

NF1 disabling mutation

Gain of proto-oncogene function

Loss of tumor-suppressor function

RAS remains excessively active

Normal RAS is inadequately inactivated

Pro-growth output rises

Pro-growth output also rises

The same signaling endpoint may arise from opposite classes of gene alteration.

Slide 30 · Two major RAS-linked kinase cascades

Active RAS

RAF

MAPK signaling

Transcription

PI3K

AKT

Metabolism / survival

The MAPK route and the PI3K/AKT route are major effectors of receptor signaling. • Both include kinase steps and generate pro-growth biological responses.

Slide 31 · RAF links RAS to the MAPK pathway

RAS–GTP

RAF kinase

MAPK kinase relay

RAF proteins are serine/threonine kinases positioned upstream in the MAPK cascade.

RAS-mediated activation of RAF initiates a relay of additional kinases.

An activated upstream kinase can influence multiple downstream targets.

Slide 32 · The MAPK relay conveys signals toward the nucleus

RAF

MAPK cascade

Transcription factors

Pro-growth genes

Sequential phosphorylation within the MAPK cascade propagates receptor-derived growth signals.

Downstream activity ultimately regulates transcription factors and pro-growth genes.

Slide 33 · Transcriptional output connects kinase activity to cycling

MAPK output

Nuclear transcription

Cyclin / growth programs

Cell-cycle progression

The MAPK cascade acts upstream of gene expression changes that support proliferation.

This supplies a mechanistic link between membrane signaling and cell-cycle entry.

Slide 34 · MYC is one downstream growth-response example

The adjacent Robbins section identifies MYC as a rapid, transient response to RAS/MAPK signaling.

MYC participates in transcriptional programs supporting growth and cell-cycle progression.

Detailed MYC oncogenic mechanisms belong to the next topic rather than this pathway lecture.

RAS / MAPK

MYC induction

Growth-supporting genes

Slide 35 · Activating BRAF alterations sustain MAPK signaling

Mutant BRAF

Constitutive MAPK signaling

Pro-growth transcription

BRAF is a member of the RAF serine/threonine kinase family.

Oncogenic activation stimulates kinases further downstream and increases transcription-factor activity.

An oncogenic lesion below RAS can bypass the normal need for RAS stimulation.

Slide 36 · BRAF is highly recurrent in hairy cell leukemia

≈100%

Hairy cell leukemia (close to)

The Robbins extract reports BRAF mutation in close to 100% of hairy cell leukemias.

This illustrates strong selection for a MAPK-pathway driver in a particular neoplasm.

Mutation prevalence is a molecular observation, not a surrogate for microscopic diagnosis.

Slide 37 · BRAF is also prominent in melanoma

~60%

Melanoma

The Robbins extract reports BRAF mutation in approximately 60% of melanomas.

An altered MAPK signaling node provides a therapeutic target in selected advanced melanomas.

Prevalence is not equivalent to a predicted individual treatment response.

Slide 38 · Oncogenic MAPK lesions cluster near the top

RAS / BRAF lesions

Multiple downstream kinase steps

Many transcriptional effects

The text observes that mutations downstream of BRAF are less common in cancer.

Its interpretation: Lesions near the cascade origin can efficiently generate broad progrowth outputs.

Pathway topology helps explain the prominence of upstream driver mutations.

Slide 39 · MAPK is a cascade rather than a single protein

Concept

Why the distinction matters

RAS nucleotide switch

Controls the initial signaling state

RAF kinase activation

Translates RAS input into a kinase relay

MAPK signaling cascade

Propagates signals through sequential enzymes

Transcription-factor response

Produces changed gene expression

Slide 40 · PI3K is recruited to membrane-associated complexes

Activated RTK

Membrane signaling complex

PI3K

AKT

After RTK activation, PI3K is recruited to signaling complexes near the plasma membrane.

PI3K serves as an upstream node of a kinase network including AKT.

Receptor recruitment helps localize the PI3K activation response.

Slide 41 · PI3K/AKT forms a second major growth pathway

RTK / RAS inputs

PI3K

AKT

Growth and survival

PI3K activation leads to downstream serine/threonine kinase signaling.

AKT is a principal effector linking receptor signaling to diverse cellular processes.

Slide 42 · AKT is a central signaling node

>150

AKT protein substrates

AKT is described as phosphorylating more than 150 proteins.

Its numerous substrates account for coordinated regulation of growth, metabolism and survival.

A broad effector node can transmit one oncogenic signal to multiple downstream processes.

Slide 43 · AKT signaling supports protein biosynthesis

PI3K

AKT

MTOR regulation

Protein synthesis

MTOR is listed among key AKT-associated regulators of protein synthesis.

Enhanced protein synthesis contributes to increased cellular mass during growth.

Biomass accumulation complements cell-cycle entry.

Slide 44 · AKT signaling also impinges on apoptosis

PI3K / AKT

Apoptosis regulators

Cell survival

The pathway engages regulators of programmed cell death, including BAD, FOXO, MDM2 and IAP.

Altered survival regulation allows growth signaling to influence whether cells persist.

Proliferation alone cannot explain expansion of a viable tumor population.

Slide 45 · BAD and FOXO are AKT-regulated effectors

Downstream target

Role in signaling interpretation

BAD

Apoptosis-regulatory protein phosphorylated within AKT signaling

FOXO factors

Transcription factors participating in apoptosis regulation

Integrated effect

AKT integrates pro-growth signals with survival control

The source groups these effectors as AKT targets; This lecture does not assign unverified phosphorylation sites.

Slide 46 · MDM2 and IAP extend AKT’s survival reach

Downstream target

Function emphasized by Robbins

MDM2

Apoptosis-associated regulatory component affected by AKT

IAP

Inhibitor-of-apoptosis protein family linked to AKT

Biological interpretation

Multiple downstream effectors can alter cell survival

Slide 47 · PI3K gains of function occur in breast carcinoma

~30%

Breast carcinomas

The text reports PI3K gain-of-function mutations in approximately 30% of breast carcinomas.

These alterations affect an intracellular kinase node downstream of receptor input.

Mutation status and therapeutic selection require tumor-specific molecular interpretation.

Slide 48 · PTEN is a negative regulator of PI3K signaling

PTEN activity

PI3K pathway restraint

Controlled AKT output

PTEN is a tumor suppressor that restrains the PI3K pathway.

Loss of PTEN permits excessive activity along the PI3K/AKT branch.

Unlike PI3K oncogenic activation, PTEN-associated oncogenesis reflects lost inhibition.

Slide 49 · PTEN loss is relevant in endometrial carcinoma

Endometrial carcinoma as a common setting for PTEN mutations.

Loss of this negative regulator can drive PI3K pathway activity.

The mechanism is tumor-suppressor inactivation rather than receptor overexpression.

PTEN loss

PI3K signaling unrestrained

Growth / survival output

Slide 50 · PI3K activation and PTEN loss converge on AKT

PI3K activating mutation

PTEN inactivating mutation

Increases drive from a positive pathway component

Removes a negative pathway regulator

Gain of function

Loss of function

Elevated PI3K/AKT pathway output

Elevated PI3K/AKT pathway output

Equivalent signaling consequences can arise from different mutation classes.

Slide 51 · The MAPK and PI3K arms have overlapping outputs

MAPK signaling

PI3K/AKT signaling

Kinase relay to transcriptional activation

Kinase signaling to growth and survival effectors

Strong link to pro-growth gene expression

Links protein synthesis, metabolism and apoptosis

BRAF a prominent oncogenic node

PI3K activation or PTEN loss commonly implicated

These are emphases, not mutually exclusive functions.

Slide 52 · Increased transcription promotes cell-cycle progression

Mitogenic pathway

Pro-growth transcription

Cell-cycle proteins

Cell division

RTK–RAS–MAPK signaling leads to transcriptional induction of growth-promoting genes.

The output helps advance the cell through controlled cell-cycle transitions.

Slide 53 · Growth signaling must also supply metabolic capacity

PI3K / AKT

Metabolic growth programs

Biomass accumulation

The PI3K/AKT branch supports metabolism needed for cell growth.

Increased macromolecular synthesis accompanies proliferation rather than arising from cell division alone.

A proliferating cell requires both a cell-cycle signal and material to build daughter cells.

Slide 54 · Signaling coordinates proliferation with cell survival

Oncogenic RTK / RAS input

MAPK

Gene expression

Cell-cycle entry

PI3K / AKT

Protein / metabolism

Cell survival

MAPK-driven transcription and PI3K/AKT activity support complementary features of the growth program. • When cancer mutations make these signals persistent, growth autonomy emerges.

Slide 55 · Driver identity changes which pathway node to inhibit

Genomic context

Pathway-level treatment rationale

Mutant KRAS

Block the appropriate mutant RAS protein when targetable

Mutant BRAF

Block the oncogenic RAF kinase in suitable tumors

Mutant PI3K

PI3K isoform inhibition may be relevant in selected cancers

RTK mutation

Targeting receptor activity addresses a more upstream lesion

Slide 56 · KRAS G12C shows that RAS can be drugged

KRAS p.G12C

Mutation-specific binding strategy

Targeted inhibition

Earlier efforts to inhibit RAS were largely unsuccessful.

Approved drugs against KRAS with a glycine-to-cysteine change at residue 12.

The alteration is described as being seen particularly in lung adenocarcinoma.

Allele specificity is central: This is not treatment for every RAS variant.

Slide 57 · BRAF inhibition provides pathway-directed therapy

BRAF-driven melanoma

BRAF inhibitor

Suppressed oncogenic output

In advanced melanoma, BRAF-directed inhibitors can produce marked clinical responses.

The therapeutic approach depends on an actionable lesion in the MAPK pathway.

A pathway diagram becomes clinically useful when the disease-defining node is known.

Slide 58 · Some PI3K isoform inhibitors have clinical approval

PI3K-altered signaling

PI3K isoform inhibitor

Selected therapeutic use

The source reports development of drugs directed at PI3K isoforms.

Some are approved for treatment of selected cancers; The text does not specify regimens or response rates.

Do not infer universal effectiveness from the existence of an inhibitor.

Slide 59 · Interpret treatment effects at the altered node

Identify the alteration before predicting a logical inhibitor target.

Determine whether the lesion affects a receptor, small G protein, kinase or inhibitor.

Different alterations within one named pathway are not therapeutically interchangeable.

Molecular lesion

Biochemical mechanism

Therapeutic hypothesis

Slide 60 · Case exercise: An RTK-wild-type lung tumor

Hypothetical application

Hypothetical lung adenocarcinoma with an activating KRAS variant and no identified activating RTK variant.

Which component is the most direct autonomous signaling driver?

Why does an upstream receptor inhibitor not automatically suppress the downstream mutant?

Reasoning target

Mutant KRAS can remain active without an oncogenic RTK; Treatment requires lesion-specific assessment.

Slide 61 · Case exercise: Inherited NF1 dysfunction

Hypothetical application

Hypothetical patient with a pathogenic inherited NF1 loss-of-function alteration.

What is the normal biochemical action of neurofibromin?

Why is NF1 classified as a tumor suppressor rather than an oncogene?

Reasoning target

Neurofibromin acts as a RAS GAP; Its loss disables inhibitory signaling rather than activating a proto-oncogene directly.

Slide 62 · Case exercise: BRAF-mutant hairy cell leukemia

Hypothetical application

A molecular assay identifies BRAF mutation in a hypothetical hairy cell leukemia specimen.

Which signaling branch is implicated?

Why can a kinase lesion below RAS reproduce pro-growth effects?

Reasoning target

The RAF–MAPK branch; Active BRAF can send signals to downstream kinases without normal upstream activation.

Slide 63 · Case exercise: PI3K versus PTEN

Hypothetical application

Two hypothetical tumors show increased PI3K/AKT pathway activity: One has PI3K gain of function; Another has PTEN loss.

Which alteration involves an oncogene and which a tumor suppressor?

Explain how both can produce excess AKT pathway output.

Reasoning target

PI3K gain is oncogenic activation; PTEN loss removes negative regulation. Both can enhance AKT output.

Slide 64 · Map each molecular lesion to its mechanism

Altered component

Mutation class

Immediate pathway effect

RAS

Gain of function

Persistent GTP-bound signaling

NF1

Loss of function

Reduced GAP-mediated RAS shutdown

BRAF

Gain of function

Persistent MAPK kinase-cascade input

PI3K

Gain of function

Increased PI3K/AKT signaling

PTEN

Loss of function

Failure to restrain PI3K signaling

A robust interpretation links gene → function → pathway output.

Slide 65 · The integrated oncogenic signaling model

Activated RTK / mutant RAS

RAF / MAPK

Transcription

Proliferation

PI3K / AKT

MTOR + survival

Cell growth

Normal growth factor dependence requires transient activation and effective negative regulators. • Cancer can bypass this control by gain-of-function drivers or loss-of-function restraints.

Slide 66 · Five mechanistic conclusions

RAS is a GDP/GTP switch; GAPs terminate its activation.

Mutant RAS and loss of NF1 can both produce excessive RAS activity.

BRAF drives the MAPK transcriptional route; PI3K/AKT coordinates growth and survival.

PTEN normally opposes PI3K signaling.

Treatment selection depends on the specific altered molecule and genotype.

Slide 67 · Primary textbook source

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026).

Chapter 7, Neoplasia: “Downstream Components of the Receptor Tyrosine Kinase Signaling Pathway,” pp. 254–255.

Adjacent context: Growth Factor Receptors; Transcription Factors / MYC.